Lipids Flashcards

Question

How cholera causes severe diarrhea

Answer 1

Cholera Toxin Mechanism: Cholera toxins bind to gangliosides (such as GM1) on the intestinal epithelial cells. This binding activates adenylyl cyclase (AC), leading to an increase in the intracellular concentration of cyclic AMP (cAMP). Effect on Ion Channels: The increase in cAMP results in the opening of chloride channels (CFTR channels), leading to the uncontrolled secretion of chloride ions (Cl-) into the intestinal lumen. This also draws sodium (Na+), potassium (K+), bicarbonate (HCO3-), and water into the lumen, causing extensive fluid loss. Impact on the Enteric Nervous System: The cholera toxin also affects the enteric nervous system, which further stimulates fluid secretion. Resulting Diarrhea: The consequence of these actions is secretory diarrhea, which is severe and life-threatening if left untreated. Since the diarrhea is secretory in nature, fasting does not resolve it, and rehydration therapy is critical for survival.

Answer 2

Membrane Asymmetry: The lipid bilayer of cell membranes is asymmetric, meaning that different types of phospholipids are distributed unequally between the inner and outer leaflets. Phospholipid Distribution: Phosphatidylcholine (PC) and Sphingomyelin (SP) are primarily found in the outer leaflet of the membrane. Phosphatidylethanolamine (PE) and Phosphatidylserine (PS) are found mostly in the inner leaflet. Phosphatidylinositol (PI) and other negatively charged phospholipids are also predominantly located in the inner leaflet. Examples of Membranes: The graph shows the distribution of these lipids in different membranes: human erythrocyte (red blood cell) membrane, rat liver plasma membrane, and pig platelet plasma membrane. Each shows a distinct pattern of lipid asymmetry. For example, in the human erythrocyte membrane, sphingomyelin and phosphatidylcholine are mainly present in the outer leaflet, while phosphatidylethanolamine and phosphatidylserine are largely in the inner leaflet. Functional Importance: The asymmetrical distribution of lipids plays a crucial role in various functions such as cell signaling, recognition, and apoptosis. For instance, phosphatidylserine (PS), when found in the outer leaflet, acts as a signal for apoptosis (programmed cell death).

Answer 3

Has four fused rings characteristic of its structure.

Answer 4

Weakly amphipathic: It has a small polar (hydroxyl group) region and a much larger nonpolar region, making it mostly hydrophobic. Insoluble in water: Cholesterol’s hydrophobic nature makes it useful in cell membranes, where it helps with stability and structure, but this also makes it difficult to transport in water-based environments like blood without carrier proteins. Rigid structure: The fused cyclohexane rings (in chair conformation) make cholesterol bulky and rigid compared to other lipids. Membrane disruption: Cholesterol tends to disrupt lipid packing in cell membranes, influencing membrane fluidity and stability.

Answer 5

Cholesterol's Role in Membranes: Cholesterol is an important component of cell membranes, where it modulates fluidity. It influences the temperature at which the membrane transitions from a gel state (rigid, less fluid) to a liquid crystal state (more fluid, dynamic). Gel State vs. Liquid Crystal State: The gel state occurs below the transition temperature (T_m). In this state, the hydrocarbon tails of the phospholipids are tightly packed in an organized manner, resulting in a more rigid membrane. In the liquid crystal state, which occurs above T_m, the hydrocarbon tails become more disordered and dynamic, allowing for greater fluidity within the membrane. Cholesterol's Effect on Transition Temperature: Cholesterol lowers the temperature at which the membrane shifts from the gel state to the liquid crystal state, effectively increasing membrane fluidity at lower temperatures. By positioning itself between the fatty acid tails of the phospholipids, cholesterol prevents them from packing too closely, thereby maintaining fluidity even at lower temperatures.

Answer 6

Lipid Rafts: Lipid rafts are specialized microdomains within the cell membrane that are rich in cholesterol, sphingolipids, and GPI-anchored proteins (glycosylphosphatidylinositol-anchored proteins). Cholesterol and sphingolipids create a more ordered and tightly packed environment compared to the surrounding lipid bilayer, forming lipid rafts. Association of Proteins: Lipid rafts serve as organizing centers for the assembly of signaling molecules, receptor clustering, and membrane protein sorting. Certain transmembrane proteins and GPI-anchored proteins preferentially associate with lipid rafts due to their compatibility with the raft environment. Platform Formation: Multiple lipid rafts can associate to form larger domains, sometimes referred to as raft platforms. These platforms enhance interactions between proteins, facilitating efficient signal transduction and other cellular processes. Role of Cholesterol: Cholesterol is crucial for the stability of lipid rafts, as its bulky and rigid structure helps maintain the ordered state of these domains, making them distinct from the more fluid areas of the membrane.

Answer 7

Vitamin D (illustrated in the image) Bile salts Steroid hormones

Answer 8

Fat-Soluble Secosteroids: Vitamin D is a group of fat-soluble compounds called secosteroids. Function: It plays a crucial role in increasing intestinal absorption of calcium, magnesium, and phosphate, which are important for bone health and other biological processes. Forms of Vitamin D: The most important forms are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).

Answer 9

Major Source: Synthesis of cholecalciferol (vitamin D3) occurs in the lower layers of the skin epidermis. This synthesis is dependent on sun exposure (specifically UVB radiation). Dietary Sources: Only a few foods naturally contain significant amounts of vitamin D. These include: Fatty fish (e.g., salmon, mackerel) Mushrooms that are exposed to UV light Not an Essential Vitamin: Vitamin D is considered not essential as it can be synthesized by the body given sufficient sunlight. Because of this, it is sometimes noted that vitamin D does not fit the strict definition of a vitamin, since vitamins are generally nutrients that must be obtained from the diet. Activated by two hydroxylation steps, the first in the liver and the second in the kidneys.

Answer 10

Polar Derivatives: Bile salts are polar derivatives of cholesterol, which means they are more water-soluble than cholesterol due to the addition of polar functional groups. Effective Detergents: Bile salts act as highly effective detergents, meaning they can emulsify fats and break them into smaller droplets. This increases the surface area for digestive enzymes to act upon, aiding in fat digestion. Role in Digestion: Bile salts are released into the small intestine where they help solubilize dietary lipids. This is crucial for the absorption of fats and fat-soluble vitamins during digestion.

Answer 11

Formation of Bile Salts: Cholic acid, a typical bile acid, ionizes to give its cognate bile salt. Bile salts are derived from bile acids like cholic acid, with modifications that make them more water-soluble. Amphipathic Nature: The bile salt molecule has a hydrophobic face and a hydrophilic face. The hydrophobic surface associates with triacylglycerols (fats), while the hydrophilic surface faces outward, allowing it to interact with the surrounding aqueous environment. This association of bile salts with fats forms a complex known as a micelle. Micelle Formation: Micelles are structures formed when bile salts surround lipid molecules, facilitating the emulsification of fats. The hydrophilic surface of the bile salt faces outward, making micelles water-soluble and allowing them to associate with pancreatic lipase and colipase. Fat Digestion and Absorption: Pancreatic lipase acts on the triacylglycerols in the micelles, breaking them down into fatty acids. These smaller fatty acids are then incorporated into a much smaller micelle, which can be absorbed through the intestinal mucosa into the body.

Answer 12

Cholesterol is a precursor for several potent signaling molecules, including all steroid hormones. Steroid Hormones Derived from Cholesterol: The diagram shows the pathways that lead from cholesterol to different steroid hormones. Cholesterol is first converted into pregnenolone, which serves as the starting molecule for various hormones. Classes of Steroid Hormones: Estrogens: Examples: Estrone, Estradiol Functions: Involved in the ovarian cycle and the development of female secondary sex characteristics. Androgens: Examples: Testosterone, Dihydrotestosterone Functions: Responsible for the development and maintenance of male traits and reproductive activity. Glucocorticoids: Examples: Cortisol Functions: Involved in the stress response and help to decrease inflammation. Mineralocorticoids: Examples: Aldosterone Functions: Help increase blood volume and pressure by regulating sodium and water retention. Progestogens (not highlighted here but important to note): Derived from progesterone and involved in maintaining pregnancy and the menstrual cycle.

Answer 13

Essential for Animal Life: Cholesterol is an essential component of animal cell membranes and is crucial for various biological functions. Sources of Cholesterol: It can be obtained through the diet, especially from foods of animal origin such as meat, dairy, and eggs. Cholesterol can also be synthesized de novo (internally by the body): It is the principal sterol synthesized by animals. Plants produce very little cholesterol, mainly synthesizing phytosterols instead, which are structurally similar but have different biological roles. Site of Cholesterol Synthesis: The liver (specifically hepatic cells) is the major site of cholesterol synthesis in mammals. It plays a key role in regulating cholesterol levels in the body. Cholesterol in Prokaryotes: Cholesterol is generally absent in prokaryotes (bacteria and archaea). However, some bacteria, such as Mycoplasma, require cholesterol for growth, as they lack a cell wall and depend on cholesterol for membrane stability.

Answer 14

All 27 carbon atoms of cholesterol are derived from acetyl CoA through a multi-step process consisting of three main stages: Synthesis of Isopentenyl Pyrophosphate: The first step involves the synthesis of isopentenyl pyrophosphate, an inactivated isoprene unit that serves as the key building block for cholesterol. This step occurs in the cytoplasm and involves several reactions that lead to the formation of the isoprene unit. Condensation to Form Squalene: The next step is the condensation of six molecules of isopentenyl pyrophosphate to form squalene, a linear hydrocarbon molecule. This step takes place in the endoplasmic reticulum and involves the combination of multiple isoprene units. Cyclization of Squalene and Conversion to Cholesterol: Cyclization of squalene occurs in what is described as an "astounding reaction" that involves multiple steps. Squalene is converted into a tetracyclic product, which undergoes a series of 19 additional steps to form cholesterol.

Answer 15

Cholesterol Transport: Cholesterol is carried through the bloodstream by lipoprotein particles in the form of cholesterol esters (a modified, more hydrophobic form of cholesterol). Lipoprotein particles serve to emulsify lipids so they can be transported in the blood, as lipids are generally hydrophobic and not soluble in the aqueous environment of the bloodstream. Structure of Lipoprotein Particles: Each lipoprotein particle has a core of hydrophobic lipids (such as an oil droplet) surrounded by a shell of more polar lipids and proteins. The hydrophobic core carries nonpolar substances like cholesterol esters and triglycerides. The outer shell, made of phospholipids and proteins, interacts with the aqueous environment. Apolipoproteins: The protein components of lipoprotein particles are called apolipoproteins. These proteins help to solubilize hydrophobic lipids within the bloodstream. They also provide cell-targeting signals, helping lipoprotein particles deliver cholesterol and other lipids to specific tissues or cells in the body.

Answer 16

Cholesterol Transport: Cholesterol is carried through the bloodstream by lipoprotein particles in the form of cholesterol esters. Cholesterol esters are even more hydrophobic than cholesterol, making them more suited for transport within the hydrophobic core of lipoproteins, such as LDL (Low-Density Lipoproteins). The cholesterol esters are trapped in the LDL particle, making LDL an efficient transporter of cholesterol to different tissues. Cellular Uptake via LDL: LDL particles enter cells through a process called receptor-mediated endocytosis. This process involves the binding of LDL particles to specific receptors on the cell surface, which triggers endocytosis. Endocytosis: Endocytosis is the process by which cells take up large molecules or particles from the extracellular environment. During this process, the entire LDL-receptor complex is engulfed by the cell membrane and internalized into the cell, allowing the cholesterol esters to be processed and used by the cell.

Answer 17

Familial Hypercholesterolemia (FH): Normal LDL Removal: In healthy individuals, LDL particles (which transport cholesterol) circulate for approximately 2.5 days before being removed by the liver through the LDL receptors. Cause of FH: FH occurs when LDL receptors on liver cells are either non-functional or absent. As a result, LDL particles aren’t removed properly and continue circulating in the blood for extended periods. Effects: This results in a high concentration of circulating LDL particles, leading to cholesterol deposition in tissues. Such deposits contribute to atherosclerosis and an increased risk of cardiovascular diseases. Types of FH: Homozygotes (Rare Form): Individuals inherit defective LDL receptor genes from both parents, resulting in no functional LDL receptors. This severe condition leads to extremely high cholesterol levels, often resulting in severe coronary heart disease in childhood. Heterozygotes (More Common Form): These individuals inherit one normal and one defective LDL receptor gene, resulting in approximately half the normal number of LDL receptors. Cholesterol levels are still elevated, which may lead to premature cardiovascular disease in their 30s or 40s. Implications: Early detection and management are crucial for those with FH, as lifestyle modifications, medications, or even interventions like LDL apheresis can help reduce cholesterol levels and minimize cardiovascular risk.

Answer 18

Familial Hypercholesterolemia (FH): Normal Function: LDL particles (which carry cholesterol) typically circulate in the blood for around 2.5 days before they are removed by the liver through LDL receptors. Cause of FH: FH occurs when LDL receptors on liver cells are either non-functional or absent. Without functional receptors, LDL particles aren't properly removed from the bloodstream and continue to circulate for much longer than normal. Effects: The prolonged circulation of LDL leads to elevated cholesterol levels in the blood. As a result, cholesterol is deposited in various tissues, leading to atherosclerosis and other complications related to cardiovascular health due to the high concentration of circulating cholesterol. Implications: The lack of functional LDL receptors is a major risk factor for premature cardiovascular disease because it results in persistent high cholesterol levels. FH is an inherited condition, which means it can be passed down through families, making early detection and management important to prevent health issues.

Answer 19

History and Discovery: Over 100 years ago, a fatty yellowish material was found on the arterial walls of patients who had died of heart disease. This material was named atheroma, derived from the Greek word meaning "porridge," due to its soft, fatty consistency. Formation of Atheromas: Atheromas are initiated by the deposition of foam cells, which are fat-laden macrophages containing LDL particles (commonly referred to as "bad cholesterol"). The LDL particles get trapped in the arterial walls and are taken up by macrophages, which become foam cells. This accumulation leads to plaque formation within the blood vessel wall. Progression of Atherosclerosis: The buildup of atherosclerotic plaques narrows the artery, restricting blood flow, which is depicted in the image showing normal vs. partly blocked blood vessels. As the plaque grows, it causes inflammation and increases the risk of complications such as heart attacks or strokes if the plaque ruptures and forms a clot. Coronary Artery Atheroma: The photograph shows a coronary artery with an atheroma, highlighting how the buildup of cholesterol and foam cells leads to the obstruction of the artery, which can significantly compromise blood flow to the heart muscle.

Answer 20

HMG-CoA Reductase: HMG-CoA reductase is the essential control point in the cholesterol biosynthetic pathway. It is a key enzyme that catalyzes an early step in the synthesis of cholesterol, specifically converting HMG-CoA (3-hydroxy-3-methylglutaryl CoA) to mevalonate. Cholesterol Management: Inhibiting HMG-CoA reductase is a primary approach to lowering cholesterol levels in the body. This is achieved using statins, which are drugs that competitively inhibit this enzyme, reducing cholesterol synthesis. By reducing cholesterol production, statins help lower LDL cholesterol levels, which in turn reduces the risk of atherosclerosis and associated cardiovascular diseases, such as heart attacks and strokes. Statins as Cholesterol-Lowering Agents: Statin drugs are widely used to treat heart disease by targeting and inhibiting HMG-CoA reductase. Lovastatin, one of the first statins, was discovered from a compound in fermentation broth of Aspergillus terreus. Lovastatin and other statins, like simvastatin and atorvastatin (Lipitor), are competitive inhibitors of HMG-CoA reductase. They mimic the structure of HMG-CoA, effectively competing for binding to the enzyme and blocking cholesterol synthesis. Mechanism of Action: Statins work by resembling the structure of HMG-CoA, the natural substrate for HMG-CoA reductase. The part of the statin molecule that is similar to 3-hydroxy-3-methylglutaryl (HMG) is highlighted in blue. This similarity allows statins to bind to the enzyme's active site with high affinity, preventing the conversion of HMG-CoA to mevalonate, an early step in cholesterol synthesis. Ki (inhibition constant) for lovastatin is 1 nM, indicating very high potency as an inhibitor. Examples of Statins: Lovastatin (brand name Mevacor) and Simvastatin (brand name Zocor) are structurally similar and act by blocking cholesterol synthesis. Atorvastatin (brand name Lipitor) is another commonly used statin, which is one of the most potent inhibitors of HMG-CoA reductase. Significance: By inhibiting HMG-CoA reductase, statins effectively reduce the production of cholesterol, particularly LDL cholesterol (often called "bad cholesterol"). Lowering LDL cholesterol levels helps to reduce the risk of atherosclerosis, thereby decreasing the likelihood of heart attacks and strokes.

Answer 21

Role of Bile Salts: Dietary lipids are solubilized by bile salts, which are amphipathic molecules synthesized from cholesterol in the liver and secreted from the gallbladder. Bile salts help break down large fat globules into smaller emulsified fat droplets, facilitating digestion and absorption. Loss of Bile Salts: Loss of bile salts reduces the total cholesterol content in the body. Bile Salt Sequestrants: Bile salt sequestrants are substances that inhibit the intestinal reabsorption of bile salts. These are orally administered positively charged polymers, such as cholestyramine, which bind negatively charged bile salts and are not themselves absorbed.

Answer 22

A triacylglycerol is formed from ester bonds between the carboxyl groups of fatty acids and the hydroxyl groups of glycerol.

Answer 23

Triacylglycerols are highly concentrated stores of metabolic energy: - highly reduced (lots of electrons) - non-polar, and so anhydrous (not much water)

Answer 24

Energy Yield from Complete Oxidation: Fatty acids (triacylglycerides, TAGs) provide approximately 37 kJ per gram. Carbohydrates and proteins provide approximately 17 kJ per gram. Therefore, fat yields more than twice the energy compared to carbohydrate or protein stores. Glycogen Storage: Glycogen is not stored in a pure form; it binds water. 1 gram of dry glycogen binds 2 grams of water, meaning that only one-third of the stored glycogen mass is actual carbohydrate, while two-thirds is water. The actual energy yield from glycogen stores is roughly 5.6 kJ per gram (since 17 kJ/g × 1 3 = 5.6 kJ/g 17kJ/g× 3 1 =5.6kJ/g). As a result, fat yields about 6.5 times more energy compared to glycogen.

Answer 25

Fat is the major energy storage form in most organisms. Major energy storage forms in a typical 70 kg male human. Triacylglycerols have a weight of approximately 15,000 g, an energy content of about 37 kJ/g, and a total energy of around 555,000 kJ. Protein stores weigh around 6,000 g, with an energy content of 17 kJ/g, totaling roughly 100,000 kJ. Glycogen weighs about 400 g, with 17 kJ/g of energy, giving a total of 6,800 kJ. Glucose weighs around 20 g and has the same energy content as glycogen (17 kJ/g), giving a total of 340 kJ. The total energy stored is about 662,140 kJ.

Answer 26

Synthesis: Triacylglycerols are synthesized in the liver. They are then transported through the bloodstream via very low-density lipoproteins (VLDLs). Diet: Dietary fats are broken down in the stomach, with bile salts from the gallbladder acting as emulsifiers. The pancreas secretes hydrolytic enzymes into the small intestine to break down dietary triacylglycerols. Triacylglycerols are absorbed and transported through the lymph and bloodstream via chylomicrons. Adipose Tissue: Stored triacylglycerols are released as free fatty acids. These free fatty acids are transported in the bloodstream bound to serum albumin.

Answer 27

Lipoprotein Particles: These particles are responsible for emulsifying lipids, making them suitable for transport through the bloodstream, which is an aqueous medium. Structure of Lipoprotein Particles: Each lipoprotein particle has a core that consists of hydrophobic lipids, which includes cholesterol esters and triacylglycerols. This core is surrounded by a shell of more polar lipids (e.g., phospholipids) and proteins. The outer shell contains phospholipids with a hydrophilic head that interacts with the aqueous environment, while the hydrophobic tails face inward. Cholesterol and apolipoproteins (proteins on the surface) are embedded within the shell, making the particle soluble in the bloodstream. Functions of Apolipoproteins: These protein components (also called (apo)lipoproteins) have two key roles: Solubilizing Hydrophobic Lipids: They help emulsify the hydrophobic lipids for transport in the blood. Cell-Targeting Signals: They serve as signals that help target the lipoprotein particle to specific cells, allowing for the delivery of lipids where they are needed.

Answer 28

Cholic Acid to Bile Salts: Cholic acid, a type of bile acid, ionizes to form its bile salt, which has both hydrophobic and hydrophilic surfaces. Bile salts are crucial in emulsifying fats. Bile Salt Complexes with Lipids: The hydrophobic surface of the bile salt binds with dietary fats like triacylglycerols. These complexes then aggregate to form micelles. Formation of Micelles: The micelles, which have bile salts with their hydrophilic sides facing outwards, allow the aggregation to be water-soluble. This enables interaction with pancreatic lipase/colipase. Digestion and Absorption: Lipase acts on the triacylglycerols, releasing fatty acids. These fatty acids then associate with smaller micelles that are absorbed through the intestinal mucosa.

Answer 29

Triacylglycerol Hydrolysis: Triacylglycerols (TAGs) must be broken down into fatty acids for absorption across the intestinal epithelium. The hydrolysis of TAGs is catalyzed by pancreatic lipases (which are enzymes secreted by the pancreas). Process of Hydrolysis: TAGs are hydrolyzed by pancreatic and gastric lipases that act on the ester bonds. Initially, TAGs are broken down into diglycerides and free fatty acids. The diglycerides are further hydrolyzed into monoglycerides and additional fatty acids. Enzyme Role: Pancreatic lipase and gastric lipase work in tandem to break the ester bonds between the fatty acyl chains and the glycerol backbone.

Answer 30

Lipid Hydrolysis in the Lumen: Triacylglycerols (TAGs) are hydrolyzed in the lumen by lipases (enzymes), breaking them down into fatty acids and monoacylglycerols. Water (H₂O) is used during hydrolysis, catalyzed by lipases. Absorption into Mucosal Cells: The fatty acids and monoacylglycerols pass through the intestinal epithelial membrane and are absorbed into the mucosal cells. Inside the mucosal cells, these components are re-esterified back into triacylglycerols. Formation of Chylomicrons: The re-formed TAGs combine with other lipids and proteins to form chylomicrons. Chylomicrons are large lipoprotein particles that facilitate the transport of lipids through the lymphatic system. Chylomicrons consist of a core containing TAGs and cholesterol esters, surrounded by a phospholipid layer and proteins, with the hydrophilic heads facing outward and hydrophobic tails inward, making the particles suitable for transport in the aqueous environment of the body. Transport to Lymphatic System: The chylomicrons are then transported into the lymphatic system before eventually entering the bloodstream, allowing dietary lipids to be delivered to tissues throughout the body.

Answer 31

Chylomicrons in the Bloodstream: Chylomicrons are transported through the bloodstream after being absorbed into the lymphatic system and released into circulation. These lipoprotein particles contain triacylglycerols, which need to be delivered to tissues such as adipose and muscle cells. Binding to Lipoprotein Lipase: Chylomicrons bind to membrane-bound lipases located on the surface of endothelial cells of adipose tissue and muscle cells. The lipase enzyme involved is known as lipoprotein lipase. The chylomicron interacts with lipoprotein lipase through Apo C-II, an apolipoprotein present on its surface, which acts as a cofactor and activates the enzyme. Hydrolysis of Triacylglycerols: Lipoprotein lipase hydrolyzes the triacylglycerols within the chylomicrons, breaking them down into free fatty acids and glycerol. The free fatty acids are then taken up by the surrounding muscle or adipose cells, where they can be used as an energy source or stored as fat. Glycerol can also be taken up and used for gluconeogenesis or other metabolic processes in the liver. Role of Lipase and Endothelial Cells: The lipoprotein lipase is anchored to the endothelial cell surface via polysaccharide chains. This allows efficient breakdown and release of the TAGs from the chylomicrons while they circulate in the capillaries close to the target tissues.

Answer 32

Exogenous Pathway (Left Side) Dietary Intake: Dietary fats and cholesterol are absorbed in the intestine. Chylomicrons Formation: Dietary fats are packaged into chylomicrons which are transported via the lymph and enter the bloodstream. Hydrolysis in Capillaries: In capillaries, chylomicrons are hydrolyzed by lipoprotein lipase, breaking down triacylglycerols into free fatty acids and glycerol. Remnant Chylomicrons: After hydrolysis, the remnants of chylomicrons, including cholesterol, are taken up by the liver. Endogenous Pathway (Right Side) Liver Biosynthesis: The liver synthesizes fats and cholesterol, releasing them into the bloodstream as VLDL (very low-density lipoproteins). VLDL Conversion: VLDL is hydrolyzed in capillaries by lipoprotein lipase, forming IDL (intermediate-density lipoproteins) and eventually LDL (low-density lipoproteins). LDL Transport: LDL delivers cholesterol to peripheral tissues and is taken up by LDL receptors. HDL Role: HDL (high-density lipoprotein) transports cholesterol back to the liver, where it can be reused or excreted, completing reverse cholesterol transport.

Answer 33

Storage in Adipose Tissue: Triacylglycerols (TAGs) are stored in adipose cells within lipid droplets. When energy is required, such as during fasting or physical activity, these TAGs are broken down into their constituent components. Hydrolysis of Triacylglycerols: The breakdown of TAGs is catalyzed by a series of lipases: Adipose Triglyceride Lipase (ATGL): ATGL initiates the hydrolysis of TAGs into diacylglycerols (DAGs) and releases a free fatty acid. Hormone-Sensitive Lipase (HSL): HSL further hydrolyzes DAGs into monoacylglycerols (MAGs), releasing another fatty acid. HSL is activated by hormones such as adrenaline and glucagon, which indicate a need for energy mobilization. Monoacylglycerol Lipase (MGL): MGL completes the breakdown of MAGs into free fatty acids and glycerol. Release and Transport: Free Fatty Acids: Once released, free fatty acids enter the blood plasma, where they bind to serum albumin for transport. They are delivered to energy-requiring tissues such as muscles, where they undergo β-oxidation to produce ATP. Glycerol: Glycerol is also released into the bloodstream. It can be taken up by the liver for gluconeogenesis (production of glucose) or for glycolysis. Hormonal Regulation: The hydrolysis of TAGs is regulated by hormones such as adrenaline, glucagon, and insulin. Adrenaline and glucagon activate HSL, promoting lipolysis when the body needs energy. Insulin, on the other hand, inhibits HSL, promoting fat storage when there is sufficient energy available.

Answer 34

Fat Cell (Adipose Tissue) Breakdown: Triacylglycerol is broken down into glycerol and fatty acids. Glycerol: Glycerol travels to the liver. In the liver, glycerol can enter glycolysis to form pyruvate or be used in gluconeogenesis to produce glucose. Fatty Acids: Fatty acids are transported to other tissues where they undergo fatty acid oxidation. Fatty acid oxidation results in the production of acetyl CoA. Acetyl CoA then enters the Citric Acid Cycle (CAC), where it is oxidized to produce CO₂ and H₂O.

Answer 35

Fatty Acid Solubility: Fatty acids are not soluble in water. Transport Mechanism: Fatty acids are transported bound to the protein serum albumin. Role of Serum Albumin: Mammalian serum albumins are crucial in binding and transporting molecules that are insoluble in water. These include: Fatty acids (e.g., released from adipose tissue) Hydrophobic hormones (e.g., thyroxine) Many drugs (affecting their dosage and distribution) Metal ions (e.g., calcium, magnesium, zinc, and copper)

Answer 36

Fatty Acid Release: Fatty acids (FAs) are released from serum albumin, which carries them in the bloodstream, and then taken up by cells of energy-requiring tissues. Original Belief: Initially, it was thought that fatty acid uptake occurred largely by passive diffusion, driven by a concentration gradient. Current Understanding: It is now understood that the uptake is mostly facilitated by proteins, which play different roles: Some proteins increase the local concentration of fatty acids near the cell membrane to improve diffusion. Other proteins directly transport fatty acids across the membrane. Diagram Components: Albumin: Releases fatty acids (FA). CD36 and FABPpm (Fatty Acid-Binding Protein, Plasma Membrane): Involved in facilitating fatty acid uptake (steps 1-3). ACS1 (Acyl-CoA Synthetase 1): Converts FA to fatty acyl-CoA (step 4). FATP1 (Fatty Acid Transport Protein 1): Helps transport fatty acids and convert them into their active forms (steps 4-5). FABPc (Fatty Acid-Binding Protein, Cytoplasmic): Binds fatty acids inside the cell for further metabolism.

Answer 37

Transport into the Mitochondria: Arrival in the Cytoplasm: Fatty acids from the diet and adipose tissue enter the cytoplasm of cells. Mitochondrial Degradation: Degradation of fatty acids occurs within the mitochondria. Activation and Transport: Fatty acids are activated (typically by converting to fatty acyl-CoA) and then transported into mitochondria for degradation. Degradation (Topic 4): Stepwise Breakdown: Fatty acids are broken down in a step-by-step manner into acetyl-CoA. During this process, some energy is released in the form of electrons. Citric Acid Cycle: Acetyl-CoA enters the citric acid cycle (Krebs cycle), where the remaining energy is extracted as more electrons, which will eventually be used to generate ATP.

Answer 38

Activation of Fatty Acids: Thioester Linkage Formation: Fatty acids must first be activated by forming a thioester linkage to Coenzyme A (CoA). Location: This activation takes place on the outer mitochondrial membrane. Enzyme Involved: The process is catalyzed by long-chain acyl-CoA synthetase in two steps. ATP Requirement: The activation is driven by ATP. Chemical Bond Formation: The carboxyl group of the fatty acid is linked to the sulfhydryl group of CoA, forming fatty acyl-CoA. Transport into Mitochondria: Once activated, the fatty acyl-CoA needs to be transported into the mitochondrial matrix for β-oxidation. Carnitine Shuttle System: CPT I (Carnitine Palmitoyltransferase I): Located on the outer mitochondrial membrane, CPT I facilitates the formation of fatty acyl-carnitine by transferring the acyl group to carnitine. Translocase: This enzyme facilitates the transport of fatty acyl-carnitine across the inner mitochondrial membrane. CPT II (Carnitine Palmitoyltransferase II): On the inner mitochondrial membrane, CPT II converts fatty acyl-carnitine back to fatty acyl-CoA and releases carnitine, which can then be reused.

Answer 39

Activation of Fatty Acids: Before entering the mitochondria, fatty acids must be activated. This involves forming a thioester bond with Coenzyme A (CoA) to produce fatty acyl-CoA. Conjugation with Carnitine: To cross the mitochondrial membrane, fatty acids are conjugated to carnitine. This conjugation allows the transport of fatty acids across the impermeable inner mitochondrial membrane and into the mitochondrial matrix. Enzymes Involved: Carnitine Acyltransferase I (CPT I): Located on the outer mitochondrial membrane, CPT I transfers the acyl group from fatty acyl-CoA to carnitine, forming acyl-carnitine. Translocase: A transport protein that shuttles acyl-carnitine across the inner mitochondrial membrane into the mitochondrial matrix. Carnitine Acyltransferase II (CPT II): Located on the inner mitochondrial membrane, CPT II transfers the acyl group from acyl-carnitine back to CoA, regenerating fatty acyl-CoA for β-oxidation.

Answer 40

Triacylglycerol Solubilization by Bile Salts: Bile Salts: Triacylglycerols are solubilized by bile salts in the intestine. Bile salts, made from cholesterol, help emulsify fats, making them more accessible for digestion. Transport by Chylomicrons: After digestion and absorption in the intestine, triacylglycerols are reassembled and packaged into chylomicrons. Chylomicrons are a type of lipoprotein particle that solubilizes and transports triacylglycerols from the intestine to various tissues via the lymphatic and circulatory systems. Fatty Acid Transport by Serum Albumin: Fatty acids released from adipose tissue are transported through the bloodstream by serum albumin. Serum albumin is a water-soluble protein that binds to fatty acids, enabling their solubilization and transportation in the aqueous environment of the blood. VLDL Transport: Triacylglycerols synthesized in the liver are transported by very-low-density lipoproteins (VLDLs), which are another type of lipoprotein particle. VLDLs carry newly synthesized triacylglycerols to other tissues for energy use or storage.

Answer 41

Obesity is defined as a medical condition in which excess body fat (adipose tissue) accumulates to an extent that it may negatively impact health. Health Risks Associated with Obesity: Obesity increases the risk of several diseases and health conditions, particularly: Cardiovascular diseases Type 2 diabetes Obstructive sleep apnea Certain types of cancer Osteoarthritis Depression Causes of Obesity: Obesity is typically caused by a combination of factors, including: Excessive food intake Lack of physical activity Genetic predisposition It can also be caused by endocrine or mental disorders, or certain medications.

Answer 42

White Adipose Tissue (WAT): WAT primarily serves as an energy storage depot, storing fat in the form of triglycerides. It also provides insulation and cushioning for the body. Brown Adipose Tissue (BAT): BAT is specialized for thermogenesis, or heat generation. It contains numerous mitochondria, which allow it to convert energy into heat, helping regulate body temperature. Brown Fat (BAT) appears more cellular and has numerous small lipid droplets and mitochondria, giving it a darker appearance. White Fat (WAT) has larger, unilocular lipid droplets, with the nucleus pushed to the periphery, giving it a more uniform and empty appearance.

Answer 43

Proportion of Body Weight: In healthy humans, white adipose tissue comprises approximately 20% of body weight in men and 25% in women. Functions of White Adipose Tissue: Energy Storage: WAT serves as a primary energy reserve, storing energy in the form of triglycerides. Thermal Insulation: WAT acts as an insulator, helping maintain body temperature by reducing heat loss. Impact Buffering: It cushions and protects internal organs and structures, acting as a shock absorber. Structural Roles: WAT also provides structural support in various parts of the body. Distribution of White Adipose Tissue: The diagram illustrates the locations of white adipose tissue in the body, highlighting its various roles: Subcutaneous: Found beneath the skin, contributing to insulation and cushioning. Visceral (Perirenal, Retroperitoneal, Mesenteric): Located around internal organs, such as kidneys and intestines, providing protection. Structural Areas: Provides support in areas like joints, bone marrow, and impact-bearing regions. Pericardial and Gonadal: Found around the heart and reproductive organs, contributing to both cushioning and endocrine functions.

Answer 44

Abundance: BAT is especially abundant in newborn humans and hibernating mammals, where it plays a key role in maintaining body temperature. BAT is also present in adult humans and remains metabolically active, though its prevalence decreases with age. Location: BAT is predominantly found around vasculature and internal organs, which allows it to efficiently release heat where needed. Primary Function: The primary role of BAT is thermoregulation through the generation of heat, a process known as non-shivering thermogenesis. This is particularly important for newborns who cannot shiver to maintain body temperature. Capillary Density: BAT contains more capillaries than white adipose tissue (WAT), which helps supply the tissue with oxygen and nutrients and effectively distribute the generated heat throughout the body. Images: The slide includes a coronal MRI image highlighting BAT distribution in the human body (visible as darkened areas), as well as comparative diagrams of white adipose tissue and brown adipose tissue showing differences in capillary density. BAT has a denser capillary network, which facilitates its heat-generating function.

Answer 45

Adipocytes are also known as lipocytes or fat cells. They are the primary constituent of adipose tissue, responsible for storing energy in the form of fat. Types of Adipocytes: There are two general types of adipocytes, each with distinct characteristics and functions: White Adipocytes: White adipocytes store energy in a single large lipid droplet, which occupies most of the cell's volume. They also have important endocrine functions, releasing hormones and signaling molecules involved in metabolism. Brown Adipocytes: Brown adipocytes store energy in multiple small lipid droplets and contain numerous mitochondria. Their primary function is to generate body heat through a process called thermogenesis, which is facilitated by the high mitochondrial content. Diagrams: The slide includes diagrams showing the structural differences between white and brown adipocytes: White Adipocyte: Characterized by a large single lipid droplet with a small nucleus pushed to the side and relatively few mitochondria. Brown Adipocyte: Contains many small lipid droplets, a centrally located nucleus, and numerous mitochondria, which give it a darker appearance.

Answer 46

White Adipocytes: Prevalence: White adipocytes are numerous in obese individuals due to their role in energy storage. Mitochondria Density: They have a low mitochondria density, which is characteristic of their primary function in energy storage rather than energy expenditure. Lipid Droplet Structure: One large lipid droplet occupies most of the cell's volume, pushing the nucleus to the periphery. Function: The primary role of white adipocytes is to store energy in the form of triglycerides. Endocrine Function: White adipocytes are endocrinologically active, expressing receptors for insulin, sex hormones, norepinephrine, and glucocorticoids, which play a role in metabolic regulation. Brown Adipocytes: "Anti-Obesity" Function: Brown adipocytes are considered "anti-obesity" due to their ability to expend energy as heat. Mitochondria Density: They have a high mitochondria density, which gives them their characteristic brown color due to the iron content in the mitochondria. Lipid Droplet Structure: Brown adipocytes contain numerous small lipid droplets, which are used as fuel for heat production. Function: They are specialized to produce heat through a process called thermogenesis, which helps in temperature regulation and energy dissipation. Endocrine Functions: Like white adipocytes, brown adipocytes also have endocrine functions, though their primary role is heat production. Illustrations: The diagrams show the structural differences: White Adipocyte: A single, large lipid droplet with a peripheral nucleus and few mitochondria. Brown Adipocyte: Multiple smaller lipid droplets, high mitochondrial content, and a centrally located nucleus.

Answer 47

Involuntary Muscle Contraction: Shivering thermogenesis involves the involuntary contraction of skeletal muscles to generate heat. These rapid, small muscle contractions increase metabolic activity, thereby producing heat to maintain body temperature. Response to Cold: All mammals exposed to cold will initially start to shiver as a reflexive response to increase heat production and maintain core body temperature. Hibernating Mammals: This process is crucial for hibernating mammals to raise their body temperature when they emerge from hibernation, ensuring a rapid return to an active state. Intensity in Adult Humans: In adult humans, shivering can reach intensities that are equivalent to up to 40% of maximum oxygen consumption, indicating significant energy expenditure for heat production. Oxidation of Energy Sources: Shivering thermogenesis involves the oxidation of mainly carbohydrates and lipids, providing the energy needed for muscle contractions and thereby generating heat.

Answer 48

Heat Production: Shivering thermogenesis can increase heat production by 3 to 4 times and raise the core temperature by approximately 0.5°C in humans. This significant increase in heat generation helps maintain body temperature in cold environments. Inefficiency of Shivering as a Heating Method: Although shivering effectively produces heat, it is considered an inefficient method of warming the body for several reasons: Convective Heat Transfer: The increased muscle activity during shivering leads to increased blood flow, which can result in greater convective transfer of heat away from the core to the periphery, reducing the efficiency of heat retention. Heat Loss Due to Movement: The gross bodily movement associated with shivering can enhance convective heat loss to the environment, similar to the effect of wind chill, which exacerbates the loss of generated heat.

Answer 49

Definition: Non-shivering thermogenesis refers to heat production without muscle contractions (shivering). It is an alternative mechanism to generate body heat in response to cold exposure. Mechanism: This process is primarily carried out by brown adipose tissue (BAT). BAT's high mitochondrial content enables it to generate heat efficiently through metabolic processes. Discovery: Non-shivering thermogenesis was discovered during World War II when researchers noticed that mice living in cold (approximately -10°C) food storage rooms behaved in a peculiar way: Initially, the mice shivered constantly as a response to the cold. Eventually, they stopped shivering but continued to thrive, suggesting another mechanism for heat production. Upon examination, they were found to have an increased metabolic rate, indicating the use of non-shivering thermogenesis. Early Hypothesis: Initially, researchers thought that skeletal muscle played a primary role in this process due to its abundance in the body. Later, it was determined that BAT was responsible after observing an increase in blood flow to BAT in response to cold exposure, which facilitated increased metabolic activity and heat production.

Answer 50

Role of Brown Fat: Brown fat is crucial for keeping newborns warm since they lack the ability to generate significant heat through shivering, which is the primary method used by adults. Hypothermia Risk: Hypothermia is a major risk for newborns, particularly for those born prematurely, due to their limited capacity to maintain body temperature in a cold environment. Susceptibility to Cold: Newborn infants are more vulnerable to cold than adults for several reasons: Higher Surface Area-to-Volume Ratio: Infants have a higher surface area relative to their volume, which means they lose heat more rapidly compared to adults. Higher Head-to-Body Surface Area Ratio: The head constitutes a larger proportion of body surface area in infants, which contributes to greater heat loss. Lack of Musculature: Infants have little musculature and therefore cannot generate heat effectively by shivering. Lack of Thermal Insulation: Infants have limited subcutaneous fat and body hair, which reduces their ability to insulate against cold temperatures. Underdeveloped Nervous System: The nervous system in newborns is not fully developed, which limits their physiological responses to cold, such as vasoconstriction. Dependence on Caregivers: Infants cannot change their circumstances, such as adding clothing or moving to a warmer place, to mitigate cold exposure. They are entirely dependent on external help to maintain warmth.

Answer 51

Early Assumptions: Brown adipose tissue was known to be present in newborns and children, where it plays a significant role in heat generation. It was long believed that BAT would eventually become more like white adipose tissue (WAT) in adults, losing its thermogenic function. Accumulating Evidence: Evidence for the presence of BAT in adults began to accumulate throughout the 20th century, challenging the previous assumption that BAT disappeared or lost its functionality after infancy. Recent Confirmation: Only recently has the presence and functional role of BAT in adult thermogenesis been confirmed. Modern imaging techniques and studies have demonstrated that adults retain significant BAT activity, especially in response to cold exposure. Distribution of BAT in Adults: The slide includes diagrams that illustrate the distribution of BAT in adults, which is typically found in specific locations: Cervical (neck region) Supraclavicular (above the collarbone) Axillary (armpits) Interscapular (between the shoulder blades) Perirenal (around the kidneys) Paravertebral (along the spine) Periaortic (around the aorta) Suprarenal (above the adrenal glands)

Answer 52

Modern Imaging Technology: The detection of BAT in adults was made possible with advancements in imaging technologies that allow the visualization of both functional and structural aspects of tissues: Positron Emission Tomography (PET): This technique provides metabolic information by detecting areas of high glucose uptake, which is indicative of active BAT, as BAT utilizes glucose to produce heat. Computed Tomography (CT): CT provides structural information, showing the anatomical locations of different types of tissues, including adipose tissue. Combining PET and CT: By combining PET and CT scans, it is possible to overlay metabolic and anatomical data, giving a comprehensive view of both the activity and location of BAT in adults. This combination allows researchers to pinpoint where BAT is metabolically active within the body. Images: The slide includes multiple images showing the presence of BAT in adults: PET/CT scans showing areas of high metabolic activity, which are indicative of active BAT. Overlayed functional and anatomical data that visually depict BAT locations, such as in the cervical, supraclavicular, axillary, and abdominal regions.

Answer 53

Categorization: Adult BAT is categorized based on cell morphology and location. Both types have small lipid droplets and are rich in mitochondria, which facilitate their role in thermogenesis. Types of BAT: Classic or Constitutive BAT: Found in highly vascularized deposits. Typically located between and over the shoulder blades, in the neck, along the spinal cord, and surrounding the kidneys. Composed of smaller adipocytes with numerous small lipid droplets. This type of BAT is present from early development and plays a significant role in thermoregulation. Beige or Brite (Brown-in-White) or Recruitable BAT: Beige adipocytes can develop from white adipocytes in response to stimulation by the sympathetic nervous system (e.g., noradrenaline release). Beige adipocytes are interspersed with white adipocytes within white adipose tissue (WAT). There is greater variability in lipid droplet size compared to classic BAT. The beige appearance is due to a greater proportion of lipid droplets relative to mitochondria. This type of BAT is recruitable and can be activated or formed in response to cold exposure or other stimuli, providing an adaptive thermogenic capacity.

Answer 54

Browning of WAT: The browning process is an adaptive and reversible response to certain environmental challenges. In response to stimuli like cold exposure or β3-adrenergic agonism, white adipocytes can transform into beige or brite adipocytes. This process is known as browning. Beige adipocytes contain numerous small lipid droplets and are rich in mitochondria, similar to classic brown adipocytes. Reversibility (Whitening): The process is reversible: when the environmental stimulus is removed (e.g., when the body is in thermoneutrality or exposed to a high-fat diet), the beige adipocytes can revert back to white adipocytes, losing their thermogenic characteristics. Characteristics of Beige/Brite Adipocytes: Beige or brite (brown-in-white) adipocytes express UCP1 (uncoupling protein 1) and contain numerous mitochondria, which enables them to engage in non-shivering thermogenesis. These beige adipocytes develop from WAT in response to stimuli like cold exposure, allowing the body to adapt to increased energy demands for heat production. Capacity for Thermogenesis: The browning of WAT increases the body's capacity for non-shivering thermogenesis, which plays an important role in regulating body temperature and maintaining energy balance.

Answer 55

Role of Mitochondria: Mitochondria in eukaryotic cells use oxidative phosphorylation to produce energy in the form of ATP. This process is crucial for generating the necessary energy for cellular functions and is also a key component of thermogenesis in BAT. Proton Gradient: During oxidative phosphorylation, energy is stored in the form of a proton gradient across the inner mitochondrial membrane. This gradient is established by the electron transport chain pumping protons (H⁺) from the mitochondrial matrix into the intermembrane space. The result is a higher concentration of protons in the intermembrane space compared to the matrix, creating both a chemical gradient and an electrochemical potential. Release of Energy: Energy is released when protons flow back across the inner mitochondrial membrane, down their concentration gradient. This flow occurs through the enzyme ATP synthase, which harnesses the energy from the movement of protons to convert ADP and inorganic phosphate (Pi) into ATP. ATP Synthesis: ATP synthase captures the energy of the proton flow and converts it into chemical energy by synthesizing ATP. In BAT, the process also involves uncoupling protein 1 (UCP1), which dissipates some of the energy as heat rather than storing it as ATP, which is key to non-shivering thermogenesis.

Answer 56

Energy Release as Heat: Instead of producing ATP, energy can be released as heat by allowing protons to flow down their concentration gradient without passing through ATP synthase. This process is called a proton leak. Role of UCP1 (Thermogenin): Uncoupling protein 1 (UCP1), also known as thermogenin, is a protein embedded in the inner mitochondrial membrane of brown adipocytes. UCP1 allows protons (H⁺) to leak across the membrane without passing through ATP synthase. This bypasses the ATP production step and instead releases the energy as heat. UCP1 is activated by fatty acids, which open the UCP1 channel to allow this proton flow and subsequent heat production. Energy Efficiency: Brown adipocytes are considered inefficient for ATP production because they prioritize heat generation over ATP synthesis. However, they are energy efficient for heat production, making them specialized for thermogenesis, especially during cold exposure. Diagram: The diagram illustrates how the electron transport chain pumps protons across the inner mitochondrial membrane, creating a proton gradient. Protons then flow back into the mitochondrial matrix through UCP1 rather than through ATP synthase. This flow results in the dissipation of energy as heat, rather than generating ATP.

Answer 57

Uncoupling Proton Transport: Endotherms (warm-blooded animals) have the capability to uncouple proton transport from ATP production to generate heat instead of synthesizing ATP. This uncoupling is a crucial process in non-shivering thermogenesis, allowing heat production without muscle activity. Specialization of Brown Adipose Tissue: Brown adipose tissue is highly specialized for non-shivering thermogenesis: Increased Mitochondrial Density: Each cell in BAT has a greater number of mitochondria compared to other cell types, enhancing its capacity for heat production. High UCP1 Concentration: The mitochondria in BAT have a higher concentration of uncoupling protein 1 (UCP1) in their inner membrane. UCP1 enables protons to bypass ATP synthase, leading to heat generation instead of ATP synthesis. Non-Shivering Thermogenesis Beyond Animals: The process of thermogenesis by uncoupling proton transport is not limited to animals. Some plants, such as those emerging in early spring when the ground is still cold, also use this mechanism. For example, Skunk cabbage can produce enough heat to melt through snow, allowing it to emerge in harsh conditions. Diagram of Brown Adipocyte: The slide includes a diagram depicting the structure of a brown adipocyte, highlighting its features: Numerous small lipid droplets and high mitochondrial density. Presence of UCP1, which enables thermogenesis. BAT's major functions include thermogenesis and certain endocrine functions (e.g., secretion of factors like FGF21).

Answer 58

DNP as a Proton Ionophore: DNP acts as a proton ionophore, which means it can shuttle protons (H⁺ ions) across cell membranes, specifically across the inner mitochondrial membrane. Dissipation of Proton Gradient: By moving protons across the inner mitochondrial membrane, DNP dissipates the proton gradient that is usually established by the electron transport chain (ETC) during oxidative phosphorylation. The proton gradient is essential for driving ATP synthesis through ATP synthase. Energy Lost as Heat: Because DNP dissipates the gradient, protons bypass ATP synthase. Instead of the energy being used to produce ATP, it is lost as heat. This process makes cellular respiration less efficient for ATP production but leads to increased heat generation, similar to the role of uncoupling protein 1 (UCP1) in brown adipose tissue. Metabolic Consequences: The presence of more DNP results in less efficient energy production, which means that the metabolic rate must increase to meet energy demands. This leads to increased fat burning as more fuel is consumed to try to compensate for the inefficiency in ATP production. This inefficiency can lead to substantial heat generation, which may cause overheating and can be dangerous or even lethal if not controlled. Regulation: UCP1 is regulated by the body to maintain appropriate heat production and energy balance, whereas DNP is not naturally regulated. This lack of regulation makes DNP particularly dangerous, as it can lead to uncontrolled hyperthermia and other adverse effects. Diagram: The diagram illustrates the action of DNP within the mitochondria: The electron transport chain creates a proton gradient, with a high concentration of protons in the crista space. DNP shuttles protons across the crista membrane into the mitochondrial matrix, bypassing ATP synthase and leading to a loss of energy as heat rather than the production of ATP.

Answer 59

Activation by the Sympathetic Nervous System: Noradrenaline (NA) is released by the sympathetic nervous system (SNS) in response to cold exposure or other stimuli that require increased thermogenesis. NA acts on β-adrenoceptors (β1, β2, β3) on the surface of brown adipocytes, with a primary effect on β3-adrenoceptors. Signal Transduction Cascade: NA binding to β3-adrenoceptors stimulates adenylyl cyclase (AC), which leads to the production of cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a key enzyme that further transduces the signal within the cell. PKA has multiple downstream effects, including activating hormone-sensitive lipase (HSL) to mobilize fatty acids (FAs) from triglyceride (TG) stores. Activation of UCP1: PKA also phosphorylates cAMP regulatory element binding protein (CREB). Activated CREB binds to the ucp1 gene and increases UCP1 expression, leading to the production of more UCP1 protein. UCP1, located in the inner mitochondrial membrane, is critical for uncoupling oxidative phosphorylation, which allows protons to leak across the membrane without generating ATP, instead producing heat. The released fatty acids also serve to activate UCP1 directly, which facilitates the oxidation of these fats, further contributing to thermogenesis. Diagram Overview: The diagram illustrates the signaling cascade: Noradrenaline (NA) from the SNS binds to β3-adrenoceptors. This binding activates AC, producing cAMP, which then activates PKA. PKA leads to phosphorylation of CREB, increasing ucp1 gene expression. Fatty acids are mobilized by HSL and utilized by UCP1 to generate heat through non-shivering thermogenesis.

Answer 60

This slide continues to explain the control of adipose tissue thermogenesis in brown adipose tissue (BAT), focusing on the detailed steps of how hormone-sensitive lipase (HSL) and uncoupling protein 1 (UCP1) contribute to heat production: Noradrenaline Activation: Noradrenaline (NA), released by the sympathetic nervous system (SNS), binds to β-adrenoceptors (β1, β2, β3) on brown adipocytes, primarily stimulating β3-adrenoceptors. This activates adenylyl cyclase (AC), increasing the production of cyclic AMP (cAMP), which then activates protein kinase A (PKA). PKA Activation and Role (Step 4): PKA phosphorylates both hormone-sensitive lipase (HSL) and perilipin, a protein that coats triglyceride (TG) lipid droplets. Phosphorylation of perilipin causes it to dissociate from the lipid droplets, exposing the stored triglycerides for hydrolysis by HSL. This leads to the activation of HSL, which catalyzes the lipolysis of triglycerides, releasing fatty acids (FAs) from TG stores. Mobilization and Utilization of Fatty Acids (Step 5): The released fatty acids (FA) serve a dual purpose: Activate UCP1 in the inner mitochondrial membrane. Enter the mitochondria, where they undergo β-oxidation to generate acetyl-CoA. Acetyl-CoA then enters the citric acid cycle, producing reduced electron carriers (FADH₂ and NADH). These electron carriers are oxidized by the electron transport chain, generating a proton gradient across the mitochondrial inner membrane. Role of UCP1 in Thermogenesis (Step 6): UCP1 functions to dissipate the proton gradient created by the respiratory chain. Instead of using this gradient for ATP production, UCP1 allows protons to flow back into the mitochondrial matrix without passing through ATP synthase. This uncoupling of oxidative phosphorylation leads to the release of energy as heat, a process known as thermogenesis. Diagram Overview: The diagram illustrates the signaling pathway: PKA activation (Step 4) leads to phosphorylation of HSL and perilipin, triggering the release of fatty acids from triglycerides. The released fatty acids are used to stimulate UCP1 and provide substrates for mitochondrial β-oxidation (Step 5). UCP1 then dissipates the proton gradient, resulting in heat production (Step 6).

Answer 61

Cold Exposure and Sympathetic Nervous System Activation: Cold exposure triggers the sympathetic nervous system (SNS), which releases noradrenaline (norepinephrine). Noradrenaline acts on β-adrenergic receptors (β-AR) located on the surface of different types of adipocytes. White Adipocytes: White adipocytes store energy as triglycerides (TG) in a large lipid droplet. Upon activation by noradrenaline, β-AR signaling leads to lipolysis, breaking down TG into free fatty acids that can be used for energy. Beige Adipocytes: Beige adipocytes are an intermediate form that can be recruited from white adipocytes under certain conditions, such as cold exposure. Noradrenaline acting on beige adipocytes leads to the activation of UCP1 (uncoupling protein 1). The pathway involves β-AR activation, which stimulates cAMP production, activating PKA, which phosphorylates CREB, thereby increasing UCP1 expression. PGC1α and BMPs (bone morphogenetic proteins) play a role in the differentiation of white adipocytes into beige adipocytes, contributing to energy expenditure. Brown Adipocytes: Brown adipocytes are specialized for thermogenesis and contain numerous mitochondria with high UCP1 content. β-AR activation by noradrenaline leads to similar signaling pathways as beige adipocytes, involving cAMP, PKA, and CREB, ultimately increasing UCP1 production. UCP1 uncouples oxidative phosphorylation by allowing protons (H⁺) to leak across the mitochondrial membrane, bypassing ATP synthase and producing heat instead of ATP. Mitochondrial Activity: The released free fatty acids are used in the mitochondria, undergoing β-oxidation to produce acetyl-CoA. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle, producing NADH and FADH₂, which are oxidized in the respiratory chain. The respiratory chain establishes a proton gradient across the inner mitochondrial membrane. UCP1 dissipates this gradient, resulting in the release of energy as heat. Energy Expenditure: Beige and brown adipocytes are crucial for non-shivering thermogenesis, which increases energy expenditure in response to cold. This process helps maintain body temperature and is part of the body's mechanism for temperature regulation.

Answer 62

Health Risks of Obesity: Obesity increases the risk of several medical conditions, including: Cardiovascular diseases Type 2 diabetes Obstructive sleep apnea Certain cancers Osteoarthritis Depression Reduction of Fat Mass: In theory, reducing fat mass can be achieved by either: Decreasing food intake (reducing caloric consumption) Increasing energy expenditure (boosting physical activity) However, achieving and maintaining fat reduction is not always simple, and the body’s physiological responses can make it challenging. Behavioral Interventions: Approaches such as dietary changes and promoting physical activity are generally effective in weight management. However, these interventions may not always be accessible or easy to maintain over time. As a result, there is growing interest in finding alternative therapeutic approaches. Pharmacological Approaches: Traditional pharmacological approaches have focused on reducing caloric intake (e.g., appetite suppressants). More recently, strategies aimed at increasing metabolic rate have been explored to combat obesity, which could involve enhancing thermogenesis in brown adipose tissue or beige adipocytes.

Answer 63

Browning Process: White adipocytes can transform into beige adipocytes in response to environmental challenges such as cold exposure. This process is called browning and is mediated by stimulation, like β3-agonism, which is linked to the activation of certain receptors due to exposure to cold. Beige adipocytes are characterized by having more mitochondria and being capable of thermogenesis (heat production), similar to brown adipose tissue (BAT). Reversibility: The browning of white adipocytes is reversible. Under conditions of thermoneutrality or high-fat diet (HFD), beige adipocytes can revert to the white adipocyte phenotype, a process known as whitening. Recruitable Adipocytes: Beige or brite adipocytes (brown-in-white) are recruitable. They are UCP1-positive and mitochondria-rich, similar to brown adipose tissue, and develop from white adipose tissue (WAT) in response to stimuli like cold. Both constitutive (brown) and recruitable (beige) brown adipocytes have a higher metabolic rate than white adipocytes, which allows for increased energy expenditure. Activation of BAT or browning of WAT leads to an increase in metabolic rate, which results in: More calories burned, contributing to increased energy expenditure. Reduction in body fat due to the breakdown of stored lipids for heat production. However, this process also leads to an increase in body temperature as the body generates more heat through thermogenesis.

Answer 64

Newborn Mice Without BAT (Knockout, K): Newborn mice without constitutive BAT show a reduced body temperature, indicating that BAT is crucial for thermogenesis, especially at an early developmental stage. The infrared images show that knockout pups have lower skin temperatures compared to control pups, further confirming the role of BAT in maintaining body heat. Adult Mice Without Constitutive BAT: Adult mice lacking constitutive BAT are able to maintain a normal body temperature at 22°C, suggesting that compensatory mechanisms may exist in neutral temperature conditions. However, when exposed to cold (5°C), adult knockout mice adapt more slowly compared to controls. The graph on the right shows that their body temperature drops significantly in response to cold exposure, particularly at the initial stages (2 hours and 48 hours). Over prolonged exposure, the temperature difference lessens but still shows impaired thermoregulation.

Answer 65

Browning of White Adipose Tissue (WAT): Adult mice without constitutive brown adipose tissue (BAT) show increased browning of some types of white adipose tissue to help with thermoregulation. UCP1 Expression: Increased expression of uncoupling protein 1 (UCP1) was observed in subcutaneous WAT (sWAT) in these mice. UCP1 is a marker of thermogenic capacity, suggesting that white fat is transforming to behave more like BAT. Increased Noradrenaline: There are also elevated levels of circulating noradrenaline (norepinephrine), which stimulates thermogenic activity, supporting the adaptive response for heat production. The western blot and graph illustrate this: Western Blot: Shows that UCP1 expression is higher in the subcutaneous WAT of knockout mice (No cBAT) compared to control. Graph: Indicates an increase in circulating noradrenaline levels in knockout mice compared to control, which correlates with the browning and thermogenic adaptation of WAT.

Answer 66

Gene Knockout and Transgenic Techniques: These techniques were used to create mice with functional β3-AR only present in specific tissues, allowing researchers to examine the effects on WAT and BAT. Groups: KO (Knockout): Mice with no β3-AR. WAT+BAT: Mice with β3-AR present in both WAT and BAT. BAT: Mice with β3-AR only in BAT. Graphs: The graphs show β3-AR mRNA levels in WAT and BAT across different experimental groups. More WAT or More BAT: The bar graphs indicate that there are differences in receptor expression depending on which adipose tissue the receptors are present in, helping illustrate the role of β3-AR in the browning process of adipose tissues.

Answer 67

Single Dose Effects: Increased Lipolysis: Although the specific data is not shown, the pharmacological activator increased the breakdown of fats (lipolysis). Increased Energy Expenditure: The activator led to a significant increase in energy expenditure, as shown by elevated oxygen consumption. Reduction in Food Intake: A 40%–50% reduction in food intake was observed in the treated rodents. Greater Effect in WAT-Positive Mice: The findings showed greater effects in mice with more WAT, suggesting these results are due to the browning of WAT and not just stimulation of existing brown adipose tissue (BAT). Graphs: The bar graphs illustrate oxygen consumption and food intake across different groups of mice, including control (CONT), knockout (KO), and transgenic lines (WAT+BAT and BAT).

Answer 68

"Hot" Therapy: Refers to the use of chili peppers, specifically capsaicinoids and non-pungent capsaicin analogues (CSNs). "Cold" Therapy: Involves mild cold exposure, set at 17°C. Experimental Design: Mice were fed a high-fat diet supplemented with capsaicin analogues and/or subjected to mild cold conditions for a duration of 8 weeks. Key Findings: Capsinoids and mild cold exposure synergistically suppressed body weight gain and increased energy expenditure. The Western blot images show increased UCP1 expression in both inguinal WAT and interscapular BAT, indicating enhanced thermogenic capacity when treated with a combination of capsaicin and cold exposure.

Answer 69

Mechanisms Involved: Cold Sensation and Capsinoid Receptor Activation: Cold exposure (17°C) is registered by thermoreceptors in the skin, which then send signals to the brain. Capsinoids, derived from chili peppers, bind to capsinoid receptors (TRPV1) in the gut. Transmission of Signals to WAT: The signals from cold exposure and capsinoids are transmitted to WAT deposits through the sympathetic nervous system (SNS), involving β-adrenergic receptors (β-ARs). Capsinoid Effects: Capsinoids stimulate an increase in β2-AR expression in WAT. They also stabilize the transcription factor PRDM16, which is a major transcriptional regulator of the transition from WAT to BAT. Cold Effects: Cold exposure stimulates the activation of β3-AR, promoting browning of WAT. Outcomes of Browning: The combined effect of capsinoids and cold leads to the development of beige adipocytes, which are known for their thermogenic capability. The browning process leads to: Increased thermogenesis (heat production). Anti-obesity effects, potentially reducing fat accumulation. Reduced fasting insulin and triglycerides (TG) in the liver.

Answer 70

Key Points: Cold and Dietary Ingredients Activation: Cold exposure and food ingredients like capsinoids and menthol can activate TRP (transient receptor potential) channels such as TRPV1, TRPM8, and TRPA1. The stimulation of these receptors sends signals to the brain. Sympathetic Nervous System Involvement: The signals from TRP receptors lead to activation of the sympathetic nervous system, which releases noradrenaline. Noradrenaline acts on β-adrenergic receptors (βAR) found in different types of adipose tissue. Impact on Adipose Tissue: White Adipose Tissue (WAT): Noradrenaline action on WAT can lead to a reduction in triglycerides (TG), contributing to decreased body fat. Beige Adipocytes: In response to noradrenaline, WAT can convert to beige adipocytes that express UCP1 (uncoupling protein 1), which helps in increasing energy expenditure. Brown Adipose Tissue (BAT): Noradrenaline also stimulates BAT, leading to the activation of UCP1. Uncoupling of Oxidative Phosphorylation: UCP1 in both beige and brown adipocytes facilitates the uncoupling of oxidative phosphorylation, allowing protons (H+) to flow through UCP1 instead of ATP synthase. This results in the release of energy in the form of heat, which is crucial for thermogenesis.

Answer 71

Key Points: Browning of WAT and Cachexia: White Adipose Tissue (WAT) browning contributes to increased energy expenditure, which is particularly notable in patients with cancer-associated cachexia. Cachexia involves the transformation of WAT to a more thermogenically active form (similar to brown adipose tissue), which leads to excessive energy expenditure and contributes to the severe weight loss observed in affected individuals. Characteristics of Cachexia: Cachexia is characterized by inflammation, body weight loss, atrophy of adipose tissue, and skeletal muscle wasting. It is common in a majority of cancer patients with advanced disease. Cachexia also occurs in end-stage conditions such as AIDS, chronic congestive heart failure, and other severe infectious diseases. Impact and Challenges: Cachexia is responsible for 20% of total deaths from cancer. Finding new therapeutic targets for cachexia prevention and treatment is critical. This involves investigating ways to prevent or reduce the browning of WAT, which could help mitigate the excessive energy expenditure and weight loss associated with cachexia.

Answer 72

Key Points: Cachexia and WAT Browning: Cachexia is characterized by systemic inflammation and the involvement of interleukin-6 (IL-6), which induce and sustain the browning of WAT. IL-6 plays a key role in stimulating the adrenal gland to release catecholamines (e.g., noradrenaline), which promotes browning. IL-6 also directly stimulates lipolysis (breakdown of fats) in WAT, contributing to the browning process. Mechanism of Browning: The slide illustrates how white adipocytes (energy-storing cells) can transform into beige adipocytes, which contain mitochondria and uncoupling protein 1 (UCP1). This transformation increases mitochondrial content and facilitates heat production instead of storing energy. Browning leads to heat production, which, while potentially beneficial in combating obesity by burning excess fat, is detrimental in cachexia as it leads to excessive energy loss and muscle wasting. Clinical Observations: Cancer cachexia patients show UCP1-positive staining in WAT, indicating the presence of thermogenically active beige adipocytes. Inhibition of WAT browning could potentially serve as a therapeutic approach to mitigate the severe weight loss and muscle atrophy experienced by cachexia patients.

Answer 73

Key Points: Adrenergic Stress and Browning: Burn trauma causes significant adrenergic stress, leading to increased levels of circulating noradrenaline. A large (10-fold) and persistent increase in noradrenaline levels occurs after burn trauma, lasting several weeks. In contrast, chronic cold exposure results in a smaller (~1.5-fold) and less persistent increase in noradrenaline. Catecholaminergic Surge: The catecholaminergic surge induced by burn trauma is suggested to contribute to the browning of WAT, increasing the metabolic activity of adipose tissue. Browning involves the appearance of more mitochondria and uncoupling protein 1 (UCP1), characteristic of thermogenically active beige adipocytes. Increased Thermogenic Capacity: Burn trauma patients demonstrate increased resting energy expenditure, increased expression of UCP1, higher numbers of mitochondria, and greater oxidative capacity compared to healthy individuals. This adaptation is likely a compensatory response to maintain normal body temperature in the absence of sufficient insulation due to the loss of the skin barrier. Diagram (Right Side): The diagram illustrates changes over time following burn trauma: 1 week post-injury: The adipocytes have mostly intact lipid droplets. 2 weeks post-injury: Increased mitochondrial activity is observed. 3 weeks post-injury: Browning is apparent with more mitochondria and UCP1 expression, indicating heightened thermogenic capacity.

Answer 74

Key Points: Burn Trauma and Adrenergic Stress: Burn trauma induces severe and prolonged adrenergic stress, which leads to increased levels of circulating noradrenaline. There is a large (10-fold) and persistent increase in noradrenaline levels that can last for several weeks following burn injury. In comparison, exposure to chronic cold results in a smaller (~1.5-fold) and less persistent increase in noradrenaline levels. Mechanism of Browning: IL-6 released from the skin during trauma stimulates the adrenal gland, which produces catecholamines (e.g., noradrenaline). These catecholamines promote the browning of subcutaneous fat, leading to increased mitochondrial content and the presence of uncoupling protein 1 (UCP1), characteristic of beige adipocytes. Impact: The browning of WAT results in increased energy expenditure and hypermetabolism, contributing to greater calorie burning. This hypermetabolic response, while helpful for thermogenesis, can be harmful in patients with burn injuries, as it exacerbates energy loss and can worsen nutritional deficits.

Answer 75

Key Points: Cold Exposure and BAT Activation: Cold exposure is a natural stimulus for activating BAT. The study involved healthy young male subjects who were categorized based on the presence of BAT: BAT (+): Subjects with substantial pre-existing BAT. BAT (–): Subjects without substantial pre-existing BAT. Study Design: Subjects were randomly assigned to two groups: One group was exposed to a cold temperature of 19°C for 2 hours. The other group remained at 27°C for 2 hours. Results: Exposure to lower temperatures increased energy expenditure in both BAT (+) and BAT (–) groups. Activation of pre-existing BAT was observed, as indicated by increased BAT activity and energy expenditure in the BAT (+) group. However, there was no evidence of new browning of WAT or generation of new BAT, suggesting that cold exposure primarily activates existing BAT rather than creating new brown adipocytes. Graphs and Imaging: The imaging on the left shows a comparison between a subject with detected BAT and a subject without detected BAT. The energy expenditure (EE) graph shows that subjects with detected BAT had significantly higher energy expenditure at 19°C compared to 27°C. The BAT activity graph indicates higher BAT activity in the detected BAT group compared to the undetected BAT group, reflecting BAT's response to cold.

Answer 76

Cold Exposure: The cold group was exposed to a temperature of 17°C for 2 hours daily for 6 weeks, while the control group continued a normal lifestyle. Results show a significant increase in energy expenditure in the cold group when exposed to 19°C after 6 weeks, suggesting increased activation of brown adipose tissue (BAT) or browning of WAT. Capsaicinoid Exposure: The study compared individuals taking capsaicinoids (active component in chili peppers) daily for 6 weeks to those taking a placebo. After 6 weeks, the capsaicinoids group showed increased energy expenditure at 19°C, which suggests that capsaicinoids may stimulate the browning of WAT.

Answer 77

Key Points: Differences in Adrenergic Receptors (AR) Between Humans and Rodents: Rodent BAT and WAT predominantly express β3-adrenergic receptors (β3-AR). In contrast, human BAT and WAT mainly rely on β2-AR for thermogenesis. Rodent β3-AR are more responsive to catecholamines than human β3-AR, making browning easier to stimulate in rodents. Challenges with β3-AR Agonists in Humans: High doses of β3-AR agonists can activate thermogenesis in humans but often have off-target effects on other receptors, which can lead to cardiac side effects. Developing agonists that are specific to human β3-AR is proving to be challenging, limiting effective methods for targeted stimulation of browning in humans. Illustrative Comparison: The diagram shows how β3-AR agonists are effective in stimulating thermogenesis in mouse BAT but do not have the same effect in human BAT, highlighting species-specific differences in receptor response.

Answer 78

Human Variability: Adult humans exhibit high variability in terms of the amount and distribution of brown adipose tissue (BAT) and WAT, as well as other metabolic differences. This variability makes it challenging to detect effects, and large sample sizes are often needed to discern true physiological signals from the background. Rodent Consistency: Laboratory rodent strains are much less variable compared to humans, which makes them better experimental subjects for studying browning because of the controlled and similar physiological parameters. Ambient Temperature Effects: The differences in housing conditions also contribute. Rodents are typically housed at temperatures below their thermoneutral zone (21°C vs 29°C), which means they are chronically exposed to cold stress. This constant cold exposure likely stimulates BAT activity and browning of WAT. Humans, on the other hand, have more control over their environmental temperature and are usually at comfortable conditions, leading to less chronic stimulation of browning processes—except in specific scenarios like cold-exposure studies.

Answer 79

Key Points: Brown adipose tissue (BAT) is metabolically active and plays a role in taking up and utilizing glucose and fatty acids. Cold exposure can lead to: Increased glucose uptake by BAT, which is reported to be even more effective than insulin at stimulating glucose uptake by skeletal muscle. Normalization of glucose tolerance in obese, glucose-intolerant mice, suggesting potential anti-diabetes effects. Increased uptake of glucose and fatty acids in existing BAT, observed in both lean and obese mice, indicating enhanced metabolic activity. Potential Roles of Activated BAT: Anti-Obesity Roles: Increased fatty acid uptake and oxidation. Activation of UCP1 (uncoupling protein 1) which is involved in thermogenesis—leading to increased energy expenditure. Anti-Diabetes Roles: Glucose uptake is enhanced, leading to reduced circulating glucose and improved insulin sensitivity. The stored energy in the form of glycogen or triglycerides is utilized for metabolism.

Answer 80

White adipose tissue (WAT) can be converted into brown adipose tissue (BAT) through certain stimuli, such as cold or capsinoid exposure. Cold exposure: Increases the conversion of white adipose tissue to brown adipose tissue, leading to increased numbers of brown or beige adipocytes. This browning process is associated with increased whole-body energy expenditure, which is beneficial for weight management and metabolic health. Mechanism: Cold and food ingredients like capsinoids stimulate transient receptor potential (TRP) channels located in the skin or gastrointestinal tract. Signals are transmitted to the brain via sensory nerves. The brain then activates sympathetic nerves, releasing noradrenaline (NA), which binds to β-adrenergic receptors (βAR). This process activates UCP1 in adipocytes, leading to thermogenesis and increased energy expenditure.

Lipids Flashcards

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