Regulation of Food Intake

What signals are orexigenic (associated with hunger/ energy conservation)?

1. Agouti-Related Protein - (Arc) 2. Endocannabinoids - (CNS) 3. Ghrelin - (gut) 4. Neuropeptide Y - (Arc) Arc- arcuate nucleus of hypothalamus

Describe the signaling of anorexigenic signals in the hypothalamus

1. Anorexigenic signals (leptin or insulin) inhibit the NPY/AgRP cells and stimulate POMC cells to release alpha-MSH in the arcuate nucleus 2. NPY and AgRP stimulate food intake via blockade of the melanocortin receptor 3. When these compounds are decreased, the melanocortin receptor is not blocked and food intake is inhibited 4. POMC cells increase the release of alpha-MSH which activates the melanocortin receptor to inhibit food intake even more

What diseases are linked to low birth weight?

1. Hypertension 2. Coronary artery disease 3. Non-insulin dependent diabetes 4. Stroke 5. Dislipidemia 6. Elevated clotting factors 7. Impaired neurodevelopment

What are the three actions of leptin signaling in the arcuate nucleus during neurodevelopment?

1. Leptin causes acute changes in neuronal activity via alteration of neuropeptide expression and release (activate POMC, inhibit NPY) 2. Leptin modifies the number and strength of synaptic inputs 3. Leptin induces neuronal projections from the arcuate nucleus to the paraventricular nucleus (diminished in leptic deficient animals)

What signals are anorexigenic (associated with satiety/ energy expenditure)?

1. Melanocyte stimulating hormone - (Arc) 2. Cocaine amphetamine-related trascript - (Arc/ LH) 3. CCK - (gut) 4. Insulin - (pancreas) 5. Leptin - (adipocytes) 6. POMC - (Arc/ LH) Arc- arcuate nucleus of hypothalamus; LH- lateral hypothalamus

What components of the hypothalamus are critical to feeding and energy balance?

1. Paraventricular nucleus 2. Lateral hypothalamic area 3. Arcuate nucleus

What are some non-hormonal orexigenic stimuli?

1. Stress, fear, celebration 2. Boredom 3. Television 4. Visual appeal 5. Odor

What is the role of AMPK on food intake?

AMPK leads to increased food intake by inhibition of mTOR whose down stream effect is anorexia. When AMPK is inhibited, ACC and mTOR are activated.

What is the Brenner hypothesis?

Adult hypertension is caused by nephron loss in utero. Decreased nephron number and increased GFR causes damage to nephrons, focal glomerulosclerosis and increase mean arterial pressure. Birth weight is a strong determinant of nephron number.

What is AgRP?

Agouti-related protein (AgRP) is an antagonist of melanocortin receptors in the hypothalamus that control energy balance. AgRP is an appetite stimulating signaling molecule.

What is Cholecystokinin?

CCK is a gut hormone that is a satiety signal. It causes gallbladder contraction, GI motility and pancreatic exocrine secretion.

What happens if there is a decrease in hypothalamic malonyl CoA?

Decrease of malonyl CoA in the basal hypothalamus caused by an overexpression of the malonyl CoA degrading enzyme (MCD), induces severe defects in hypothalamic nutrient sensing. This stimulates liver gluconeogenesis, hyperphagia and obesity.

What can cause pathologic weight gain and insulin resistance?

Defects in: 1. Secretion of insulin or leptin 2. Hypothalamic sensing of adiposity or nutrient related signals 3. Neuronal responsiveness to these inputs This can predispose a person to positive energy balance and increased glucose production.

What are the major side effects of CB-1 blockers?

Depression, anxiety, dizziness, insomnia, nausea and diarrhea.

How are endocannabinoids derived?

Diet-derived 6-polyunsaturated fatty acids (6-PUFAs) are incorporated into membrane phospholipids that can be metabolized into the two major endocannabinoids 2-AG and anandamide by membrane associated enzymes.

What abnormalities are associated with food cravings?

Feeding activates the brain's reward pathways and abnormalities here can be associated with food cravings. Brain imaging shows reductions in D2 receptors in the striatum of obese individuals. Obese individuals show abnormal activity in the prefrontal cortex (involved in motivated behavior) in response to food stimuli.

What is the thrifty gene/ phenotype hypothesis?

Fetal malnutrition --> low birth weight --> post natal overnutrition --> obese adult Adequate fetal nutrition --> thin adult

Cachexia

General physical wasting and malnutrition usually associated with chronic disease

What is Ghrelin?

Ghrelin is a gut hormone that is responsible for the hunger signal

How does Leptin resistance occur?

High/ chronic leptin signaling activates high levels of SOCS3 which shuts down leptin signaling in a feedback loop.

How are the reward and energy balance regulatory pathways integrated?

Homeostatic system of the brain consists of POMC and AgRP/NPY expressing neurons in the arcuate nucleus. These neurons project to the lateral hypothalamus where they influence neurons that project to many brain regions, including the VTA. In addition to acting on the homeostatic system, leptin and insulin can act directly on the reward system in the brain.

What is the set point theory?

Individuals are able to maintain a constant weight despite variations in day to day input. This is a mechanism that resists weight loss by changing metabolic efficiency.

How do fatty acids enter the CNS? What is their role?

LCFAs are bound to albumin in the plasma and cross the BBB by simple diffusion in the unbound form. Inside neurons, they are rapidly esterified to LCFA-CoAs that can be used by the mitochondria for FAO. Malonyl CoA availability regulates the mitochondria oxidation. Circulating LCFAs signal the bodies nutritional status to hypothalamic energy centers. They must be in the CoA form to have any effect.

What is Leptin?

Leptin is a hormone that functions in satiety. When the stomach is full, triglycerides circulate and adipocytes release leptin. Leptin is recognized by receptors in the hypothalamus and feeding is terminated.

What is the role of leptin in the arcuate nucleus?

Leptin regulates two populations of neurons in the arcuate nucleus: 1. It inhibits NPY/ AgRP neurons that are OREXIGENIC 2. Activates POMC/CART neurons that are ANOREXIGENIC

How can leptin affect endocannabinoids?

Leptin signaling can influence 2-AG biosynthesis in the hypothalamuc and anandamide hydrolysis in T-lymphocytes.

How can set point be altered?

Lesions of the lateral hypothalamus appear to reset the set point for body weight and make it lower. Animals with lesions decreased their intake and lost weight when compared to controls.

What is the effect of AMPK on Malonyl CoA?

Malonyl CoA formation by ACC is allosterically inhibited by AMPK

What is the role of malonyl CoA? In the hypothalamus?

Malonyl CoA functions as a sensor for nutrient availability in many tissues. In the hypothalamus, Malonyl CoA is induced by feeding and suppressed by fasting. Build up of Malonyl CoA promotes an anoretic response (senses fatty acids).

What are the different pathways for hypothalamic output to control feeding behavior or energy expenditure?

POMC- inhibits feeding and stimulates energy expenditure NPY- stimulates feeding and decreases energy expenditure

What are the possible therapeutic uses of CB-1 blockers?

Rimonabant was the first CB-1 receptor blocker and it caused impressive and maintained weight loss. It was pulled from the market due to increased suicidal ideation.

What is the role of CB-1 receptor?

The CB-1 endocannabinoid receptor is located mostly presynaptically and mediates the retrograde action of endocannabinoids. CB-1 signaling affects the expression of orexigenic and anoretic mediators in the hypothalamus. CB-1 receptor signaling promotes feeding.

What is the median eminence of the hypothalamus?

The median eminence is a circumventricular organ that is sensitive to many hormones, including those related to homeostasis

What is the Barker hypothesis?

The nutritional status of a pregnant mother alters the fetus with regards to the future (predicts adult disease): 1. Future appetite 2. Future weight 3. Future likelihood of cardiovascular disease

What is the postnatal leptin surge?

The postnatal leptin surge occurs at the time the hypothalamic circuits are programmed by leptin. In animal models of undernourished pregnant rats, leptin treatment for the pups 3-13 days post natally prevents the negative sequelae associated with low birth weight.

What happens to hormone signals in response to weight loss?

Weight loss can lead to significant reductions in levels of leptin, peptide YY, CCK, insulin as well as BMR and increases in levels of ghrelin and appetite. These changes persist for long after weight loss.