Satiety and Hunger Pepide and Hormone Signals

Question 1

Regulation of Lipolysis

Answer 1

• When required to meet energy needs of the body or in response to certain pathological situations, fatty acids are released from triacylglycerol via lipolysis.
• The limiting reaction in lipolysis is hormone-sensitive lipase (triacylglycerol lipase) that is regulated by covalent modification via phosphorylation.

-Hormone-sensitive lipase removes the first fatty acid from the triacylglycerol with the remaining two fatty acids being removed by either hormone-sensitive lipase or other less specific lipases.

•When phosphorylated, hormone-sensitive lipase is active and in the “a” form whereas the dephosphorylated “b” form is inactive.

Question 2

Set Point Hypothesis

Answer 2

• This proposes that blood-borne factors mediate control of body weight at a defined level (e.g., “set point”) by interacting with the hypothalamus to regulate both food intake (appetite) and energy expenditure (level of activity and body temperature). Several discrete genetic loci and their protein products have been identified. A deficiency or defect in one of these may disrupt normal body weight control, leading to dramatic weight gain and associated syndromes, such as type 2 diabetes. Indeed, 80% of type 2 diabetics are obese.
• The current model used to explain food intake is the lipostat or adipostat concept, which states that signals proportional to the size of fat stores integrate with other regulators of food intake. Depletion of energy stored in adipose tissue thereby increases food consumption. Thus, food intake is regulated within a lipostatic system for energy homeostasis.

Question 3

Other Factors Controlling Body Weight

Answer 3

•hypothalamus

• leptin receptor
• alpha MSH4 receptor
• satiety

*CART

*CCK

*GLP-I

*alpha-MSH

*serotonin

-hunger

*AGRP

*galantin

*NP-Y

*orexin A

*orexin B

•thyroid

-T₄/T₃

_•pancreas

-insulin

•adipose

• alpha MSH 1,2,3,5 receptors
• beta 3 adrenergic receptor
• resistin receptor
• PPARy
• UCP
• leptin
• resistin

Question 4

Leptin and alpha MSH when adipose stores are high

Answer 4

• The “set point” hypothesis predicts that a blood-borne factor mediates control of body weight by interacting with the hypothalamus.
• The leptin hormone system satisfies these requirements, as it consists of a blood hormone produced primarily in adipose cells (
• Leptin binds to a specific receptor found mainly in the hypothalamus.

-This leptin receptor is also expressed in tissues such as adipose and pancreas.

• Leptin is secreted by white adipose tissue into the circulation.
• From the blood it crosses the blood brain barrier, and binds to its specific membrane receptor in certain areas of the brain.
• The leptin receptor belongs to the same superfamily as the growth hormone and prolactin receptors.
• These receptors are linked to the JAK-STAT signal transduction cascade.
• Administration of exogenous leptin decreases feeding behavior, while metabolic rate, body temperature and activity level increase.
• When adipose stores are high, leptin is produced in proportion to stored energy, and circulates as a hormone to the hypothalamus.
• alpha-MSH is the downstream mediator of leptin’s actions.
• Synthesis and secretion of alpha-MSH by the arcuate nucleus of the hypothalamus are regulated positively by leptin binding to its receptor in the cell body of these special neurons. They are programmed to process proopiomelanocortin (POMC) to alpha-MSH.
• In turn, alpha-MSH suppresses appetite, and travels to the periphery to enhance metabolic activity by increasing lipolysis in adipose tissue via the MC1,2,3,5-R receptors

Question 5

Leptin and alpha MSH when adipose stores are low

Answer 5

• When adipose stores are low, such as after a period of limited food intake and metabolic fat burning, circulating leptin concentration is markedly reduced, and the leptin receptor is activated only sparingly.
• In this setting, the concentration of alpha-MSH falls and “hunger” neurons in the hypothalamus produce agouti-related peptide (AGRP) whose synthesis is normally suppressed by leptin.
• AGRP enhances appetite by antagonizing the binding of alpha-MSH to MC4-R.
• Finally, diminished peripheral alpha-MSH from POMC neurons limits fat catabolism until the adipose energy depot is replenished by the combination of this effect plus feeding behavior.
• When fat stores become “adequate,” then various controls once again operate to curb appetite and promote energy expenditure . In this fashion, body weight can be maintained within narrow limits for many years!

Question 6

What peptides does leptin suppress?

Answer 6

• Besides suppressing AGRP, leptin curbs neuropeptide Y (NP-Y), a second major appetite stimulator, as well as galanin, a “hunger peptide” in the hypothalamus similar to NP-Y. The unique feature of galanin is its ability to stimulate the appetite for fatty food, especially in adolescents reaching puberty.
• The other two hunger factors, orexins A and B, may be down regulated by leptin. These factors also appear to affect the basal metabolic rate.

Question 7

Regulation in the Adipocyte - alpha-MSH action via MC-1,2,3,5-receptors

Answer 7

• The melanocortin (MC) or alpha-MSH receptors, numbering five isoforms (1- 5), have emerged as crucial in adipose homeostasis, especially since the alpha-MSH ligand operates both centrally and peripherally in fat cell depots.
• The melanocortin 4 receptor (MC4-R) in the hypothalamus signals satiety when occupied by alpha-MSH (produced in POMC neurons in response to leptin). In the absence of leptin, the MC4-R is antagonized by the binding of the AGRP hunger factor.
• The adipose isoforms of the receptor (MC- 1, 2, 3, 5-R) are activated by circulating alpha-MSH, which is secreted from the hypothalamus, to increase cAMP.
• In turn, cAMP activates hormone-sensitive lipase (HSL) via protein kinase A (PKA) catalyzed phosphorylation.
• Hormone-sensitive lipase action liberates free fatty acids from triacylglycerols (TAGs) resulting in increased beta-oxidation to burn fat.
• Adipose cells do not burn much free fatty acids via beta-oxidation. Instead the products of hormone-sensitive lipase are released for use by liver and muscle. These tissues have much higher energy requirements.
• This process is promoted further by the uncoupling of oxidative phosphorylation via uncoupling protein.
• In summary, alpha-MSH qualifies as the key downstream mediator of leptin actions, both with respect to central satiety, as well as energy expenditure via fat burning.
• One intriguing recent finding is that alpha-MSH also represses LPL, rendering alpha-MSH the ultimate anti-fat depot hormone.

Question 8

Regulation in the Adipocyte - beta3 adrenergic receptor

Answer 8

• The beta3-adrenergic receptor is a subtype found in adipose tissue, as well as in liver and certain muscles.
• In addition to alpha-MSH activating the MC receptors in adipose cells, beta3 agonists, primarily norepinephrine from the sympathetic nervous system, increase lipolysis and thermogenesis in adipose tissue.
• A mutant form of the beta3-adrenergic receptor occurs in certain populations especially prone to obesity, (e.g., Pima Native Americans of Arizona).
• A defect in this protein would be expected to reduce hormone-stimulated lipolysis and thermogenesis in adipose tissue.
• Although there is some evidence that this is indeed the case in human patients harboring the mutation, the effect is surprisingly subtle.

-For example, among Pima Indians, the only statistically significant finding was the age of onset of NIDDM (36 for homozygotes, 40 for heterozygotes, and 41 for normal controls). Studies in other groups have generally confirmed a modest effect of this mutation.

Question 9

Regulation in the Adipocyte - Resistin

Answer 9

• Resistin, an adipose-derived hormone, causes insulin resistance.
• Resistin inhibits insulin’s stimulation of glucose uptake into adipose cells, and suppresses its enhancement of lipoprotein lipase (LPL) and inhibition of hormone sensitive lipase (Figure 4).
• Thus, resistin is a novel hormone that may be the missing link between obesity and Type II diabetes.

Question 10

Regulation in the Adipocyte - Peroxisome proliferator activated receptor gamma (PPARgamma)

Answer 10

• PPARgamma in adipose tissue binds certain arachidonate derivatives. One of the natural ligands for PPARgamma is 15-deoxy-delta 12,14 -prostaglandin J2 , while synthetic ligands include the drugs classed as thiazolidinediones (e.g., troglitazone [Rezulin; rosiglitazone [Avandia).
• PPARgamma and its ligand are involved in the promotion of insulin signaling, predominantly by suppressing resistin expression and hence plays a critical role in regulating insulin sensitivity and glucose homeostasis.
• PPARgamma together with the retinoid X receptor (RXR) binds to DNA as a heterodimer.
• Thus, combinations of an RXR ligand, or retinoid, and a PPARgamma ligand, such as rosiglitazone, may be effective in resensitizing NIDDM patients to insulin.
• Accordingly, activation of PPARgamma supports insulin-stimulated glucose transport.
• Additionally, PPARgamma and its ligand stimulate the differentiation and proliferation of adipocytes. Human mutations in PPARgamma confirm this action.

Question 11

Regulation in the Adipocyte - UCP

Answer 11

• The expression of the gene for the mitochondrial uncoupling protein (UCP) is a target gene for thyroid hormone.
• Isoforms of UCP are found in adipose tissue, skeletal muscle and other tissues.
• UCPs uncouple the mitochondrial electron transport from ATP formation.

-UCPs primarily act as proton channels to collapse the proton gradient across the mitochondrial inner membrane and thus dissipate cellular energy as heat.

• Thermogenesis via UCP may be an important mechanism for balancing energy expenditure with (excess) caloric intake.
• In humans, skeletal muscle seems to play a large role in thermogenesis.
• The UCP isoform in skeletal muscle is upregulated by thyroid hormone in a manner consistent with a role for skeletal muscle in thermogenesis.
• It is well established that hyperthyroid individuals exhibit a high metabolic rate and elevated body temperature, while the reverse effects are found in individuals who are hypothyroid.
• UCP may not be completely responsible for this effect of thyroid hormone, since thyroid hormone also induces Na/K-ATPase, and some heat is lost in the function of this enzyme during ATP utilization for ion transport.

•However, humans with mutations in various forms of the uncoupling protein exhibit obesity, reduced fat oxidation and reduced respiratory quotient.