chapter 9 Flashcards
Food and Energy Regulation
Animals eat to obtain energy
All cellular processes require energy
The brain is a major consumer of energy (i.e. glucose) and needs substantial energy to function properly
Although there are fluctuations in energy requirements as the rate of energy that we use changes during the day, over seasons and across a lifetime, the need for energy is constant
However, energy acquisition fluctuates
Problem: eating tends to be episodic while need for energy is more or less continuous
Result: energy acquisition and energy expenditure are never completely balanced
Animals have evolved complex homeostatic mechanisms to regulate short term and long term energy balance.
Involve numerous hormones and signaling molecules
Metabolism –Well Fed State
After eating a meal, there are two phases of energy utilization and storage :
Postprandial
occurs immediately after ingestion
a supply of metabolic fuels in the forms of glucose, fatty acids and amino acids enter the blood stream
Unless you are running a marathon after eating, there will be surplus energy ….
Postabsorptive:
excess energy is stored
insulin rises and glucagon falls
Postabsorptive
the 2nd phase of energy utilization & storage
excess energy is stored
insulin rises
glucagon falls
Insulin is released from the pancreas in 2 phases:
Cephalic: sensory stimuli (sight, smell, taste) evoke a conditioned release of insulin before nutrients have arrived in the digestive system
Gastrointestinal:
insulin released in response to absorption of nutrients from gut
Insulin
ONLY hormone responsible for energy storage.
Promotes uptake of glucose into tissues for oxidation (i.e. brain, muscles) and storage (i.e. liver, muscle, adipose) in the form of glycogen through the process of glycogenesis
In doing so insulin lowers blood glucose levels
Metabolism – Fasting State
Eventually, blood concentrations of glucose drop and the body must shift from putting energy into storage into getting it out of storage
Glucagon rises
Insulin falls
Which cells of the pancreas secrete glucagon?
alpha
Which cells of the pancreas secrete insulin?
beta
Glucagon
Released from pancreas
Induces glycogenolysis:
Breakdown of stored glycogen by liver.
Provides glucose that is preferentially used by the brain
Induces lipolysis:
Breakdown of lipids in adipose tissue into free fatty acids and glycerol.
Provides oxidizable fuels for peripheral tissue (i.e. muscle) thereby sparing glucose for the brain.
Amino acids in the liver can also be converted to glucose (gluconeogeneis) and ketone bodies, a secondary fuel which can be used by the brain & body
Diabetes
Type I
Insulin dependent mellitus
Autoimmune disorder in which the β cells of the pancreas are destroyed by the immune system, resulting in an insulin deficiency
Rapid onset, most common in children and young adults
Treatment involves replacement of missing insulin via injection
Diabetes
Type II
Tissues develop an insensitivity to insulin
Develops slowly in adults over the age of 40, associated with obesity
Incidence is rising among younger obese individuals
Early stages can be controlled by diet, and insulin treatment isn’t required
If left uncontrolled, can cause the pancreas to stop producing insulin, requiring the use of exogenous insulin treatment
Diabetes
Symptoms
Individuals with either type of diabetes have trouble moving surplus glucose out of the blood
Symptoms:
Elevated appetite, increased thirst & urination in an attempt to rid body of excess glucose, high blood glucose (hyperglycemia) which can lead to other health problems including neuropathy, poor circulation and blindness
Regulation of hunger & satiety
Given the crucial role of insulin in mobilizing energy you might think that the brain monitors insulin levels to decide when it is time to eat and when its time to stop
Although insulin & glucose contribute to hunger & satiety, they are not sufficient to explain those states entirely
The brain integrates insulin & glucose levels with other sources of info to regulate eating
No single region controls hunger but many findings demonstrate that the hypothalamus is critical
Hypothalamic control of feeding is complicated
For many years “Dual-center” hypothesis thought to be correct
This model proposed 2 appetite centers: one to signal hunger, the other to signal satiety
Hunger center in Lateral Hypothalamus (LH):
LH-lesioned animals displayed aphagia (refusal to eat) and weight loss
Satiety center in ventromedial hypothalamus (VMH):
VMH lesioned animals displayed hyperphagia (excess feeding) and weight gain
Appetite balancing act between hunger and satiety centers
This hypothesis proved to be too simple to account for the regulation of feeding
Hypothalamus Regulates Food Intake
Current model focuses on the Arcuate Nucleus
Has two neuronal circuits with opposite effects:
Feeding Stimulatory Circuit (Anabolic) produces two orexigenic peptides that stimulate food intake, reduce metabolism and promote weight gain:
NPY (neuropeptide Y)
AgRP (agouti related protein)
Feeding Inhibitory Circuit (Catabolic) produces two signaling molecules that inhibit food intake, increases metabolism and promotes weight loss:
POMC produces α-MSH
CART (cocaine- and amphetamine-regulated transcript)
Both circuits:
Both circuits send signals to PVN and LH which then directly modulate feeding behaviors via opposing actions
PVN inhibits feeding; LH stimulates feeding
Both circuits have receptors for peripheral signals that cross or are transported across the BBB (leptin, insulin, ghrelin, etc…)
Leptin (and to a lesser extent insulin): adiposity signals that convey info about the body’s energy reserves
High levels of leptin signal high fat stores, Low levels of leptin signal low fat stores
High leptin should lead to satiety in normal weight individuals
Low leptin should stimulate feeding
Control of Food Intake
High leptin (high energy reserves) decreases feeding behavior by inhibiting NPY/AgRP neurons and stimulating POMC/CART neurons
Inhibit feeding ‘on’ circuit;
activate feeding ‘off’ circuit
What happens when leptin levels are low?
Feeding ‘on’ circuit released from inhibition; feeding ‘off’ circuit no longer stimulated
Lesion of POMC neurons leads to over-eating and increased body weight
POMC KO is overweight (feeding inhibitory).
AGRP KO is not (feeding stimulatory)
Other signals besides leptin and insulin control hypothalamic feeding centers
Ghrelin acts to stimulate feeding by activating AGRP/NPY neurons
Many other hormones modulate the arcuate nucleus to influence feeding and satiety
NTS (nucleus of the solitary tract)
NTS (nucleus of the solitary tract) in brainstem receives & integrates appetite signals from a variety of sources beyond the hypothalamus including satiety signals:
- from the liver which detects glucose and communicates this info to the NTS via the vagus nerve
- gut peptides like CCK (cholecystokinin) which reach the NTS through the vagus nerve and sympathetic fibers
cholecystokinin
gut peptide CCK (cholecystokinin) reaches the NTS through the vagus nerve and sympathetic fibers
Hypocretin
Hypocretin (also called orexin) system in the brain
located only in Lateral hypothalamus – projects widely
Stimulation produces arousal & foraging
Mutations in this hormonal system produce narcolepsy symptoms
Hypocretin and the addictive/reinforcing properties of eating:
Hypocretin system interacts with reward & reinforcement system.
Hypocretin neurons are activated in response to rewarding stimuli such as food or addictive drugs.
Hypocretin afferents from the lateral hypothalamus innervate dopamine neurons of the ventral tegmental area (VTA).
Increase effects of glutamate neurotransmission in synapse
Hypocretin, sleep and overeating:
Significant increase in the desire for weight-gain promoting high-calorie foods following sleep deprivation.
May be due to increased hypocretin (sleep drive) leading to hunger
Gonadal hormones and body weight:
Ovariectomy leads to increases in body mass/fat in rodents
Estradiol treatment prevents; progesterone induces increased body mass.
Same is true of menopause in human women. Eating is increased during luteal phase (high P).
Direct implants of estradiol into VMH or PVN of Hypo lead to decreased body weight and food intake, suggesting direct effects of hormone on feeding centers
Estradiol also increase enzyme activity in fat tissue, leads to less fat storage; Progesterone does the opposite
Gonadectomy in males also leads to increased body mass/body fat
Obesity
65% of Americans are overweight, 31% qualify as obese (based on BMI)
Major health problem…associated with higher incidence of cardiovascular disease, diabetes and other disorders
Like it or not, our evolutionary history has optimized our bodies for obtaining and storing energy to enhance survival in environments where energy availability fluctuates
Protecting against accumulating too much energy was not a concern for our distant relatives
The tendency to accumulate excess energy is exacerbated by our sedentary lifestyles
Obesity is difficult to treat
Appetite control:
Leptin, cannabinoid antagonists (munchies)
Increase metabolism:
Thyroid hormones
Inhibition of fat tissue formation:
Angiogenesis inhibitors block adipogenesis
Reduced absorption:
Xenical interferes with digestion of fat
Reduced reward
Could leptin be used to treat obesity?
Many obese people have abnormally HIGH levels of leptin because lots of adipose tissue.
Leptin resistance (like insulin resistance)
The body is constantly in ‘starvation’ mode hormonally —-> EAT!
No amount of leptin will lead to satiety IF BRAIN IS RESISTANT.
Need to decrease leptin resistance instead
Liposuction
Anti-obesity surgery
surgical removal of fat
only moderately successful and temporarily
Fat usually regrows after excision
Bariatric surgery:
Anti-obesity surgery
bypass part of the intestinal tract or stomach in order to reduce the volume and absorptive capacity of the digestive system.
Although doesn’t directly target appetite controlling mechanisms, changes in appetite hormones accompany surgery
Produces a significant and lasting weight loss
Accompanied by significant complications and risks
Gastric bypass and hormonal changes associated with feeding/satiety
Gastric bypass sometimes fixes hunger hormones, diabetes, and metabolic health well before leading to weight loss
How does changing the endocrine state of the gut influence metabolic health?
Is gastric bypass a good strategy to help with diabetes (type 2) in non-obese individuals?
