Food Regulation Rob Contreras, Ph.D. 018 Longmire

Two Principle views of food intake control Food intake triggered by: –Depleted energy stores Less adipose tissue Less glucose or lipid –Primed to eat unless inhibited Signals from meals Onset not from acute need Caloric homeostasis

Preserve cellular metabolism Three macronutrients –Carbohydrates, lipids, proteins Most tissues of the body –COH to glucose, or lipids to free fatty acids Liver –Lipids Brain –Glucose (backup - ketone bodies)

Two Distinct Metabolic States Prandial (fed) state –Abundance of newly ingested & absorbed nutrients in blood Postabsorptive (fasted) state –Absence of entering calories from GI tract into circulation –Reliance on metabolic fuels less recently ingested and stored

Caloric homeostasis During prandial state, energy is stored – as glycogen (liver and muscle) or triglycerides (adipose tissue) – facilitated by insulin – ANABOLISM During postabsorptive state, energy is utilized for metabolism – facilitated by lack of insulin – either glycogenolysis (to produce glucose) or lipolysis (free fatty acids and glycerol) – CATABOLISM Regulation of feeding is a balancing act – between energy storage (anabolism) and use (catabolism)

Liver: Key organ in energy traffic Prandial/fed –COH to glycogen –Lipogenesis (also in adipose tissue) Postabsorptive/fasting –Glygogenolysis –Ketogenesis –Glugoconeogenesis Control system = hormones + ANS

Insulin B cells of the pancreatic islets Direct proportion to blood glucose Also amino acids & ketone bodies ANS innervates pancreatic islets –PNS (ACh) stimulates secretion –SNS (NE, alpha-adrenergic) inhibits secretion

Caloric homeostasis: Insulin Insulin is low during fasting It is increased in cephalic phase by sight, smell and taste of food When food enters stomach, there are direct actions of digestive hormones on insulin secretion – during gastrointestinal phase Substrate phase results from stimulation of pancreas by metabolic fuels (mainly glucose) Insulin serves to promote energy utilization and storage

Insulin & body fat More body fat, the more insulin secretion Number of insulin receptors on adipose tissue & skeletal tissue inversely related to adiposity Reciprocal relationship between insulin secretion & tissue sensitivity to insulin Insulin ensures efficient use & storage independent of body weight

Diabetes mellitus Type 1 or Insulin-dependent –High plasma glucose –Cannot be utilized & excess excreted -sweet urine –Caused by deficiency in B cells & insulin secretion Type 2 or noninsulin-dependent –85-90% have insulin, but are obese & resistant to insulin in promoting fuel use & storage

Two Principle views of food intake control Food intake triggered by: –Depleted energy stores Less adipose tissue Less glucose or lipid –Primed to eat unless inhibited Signals from meals Onset not from acute need Caloric homeostasis

Caloric homeostasis and food intake: Satiety Meal size does not depend on time since the last meal – however, the size of a meal determines how long before the next one Eating appears to be inhibited by a “satiety signal” that decreases over time

Caloric homeostasis and food intake: Satiety factors Gastric distension serves as one satiety signal: Rats with gastric fistulas, which do not allow fluid into the stomach, do not terminate meals as readily Cholecystokinin (CCK) is secreted by the stomach during meals and also serves as a satiety factor Several other molecules, including insulin, bombesin-like peptides, and glucagon may also be satiety factors – these factors control meal size

Satiety Signals Gastric distention –Stomach endowed with stretch receptors –Vagus to NST & area postrema Cholecystokinin –Secreted during meals –Receptors on Vagal afferent fibers that also convey gastric stretch signals –CCK + stretch act synergistically to inhibit food intake Post-gastric –Nutritional signals from intestines to liver Body Weight –Forced weight loss or weight gain

Body weight and food intake: Leptin 4) Ingestion of food generates satiety signals; L- and I- sensitive pathways interact with satiety circuits to regulate meal size 3) Low leptin and insulin in brain stimulate eating and suppress energy expenditure 2) Leptin and insulin suppress brain anabolic circuits and activate catabolic circuits 1) Leptin and insulin circulate in proportion to body fat and energy balance

Body weight and food intake: Leptin Mutants of the Ob-Rb receptor (for leptin) are both hyperphagic and obese – i.e., they do not detect circulating leptin and overeat Leptin is secreted by adipocytes and circulates in proportion to the amount of body fat

Overton lab goal is to determine mechanisms linking regulation of energy balance and cardiovascular function Overfeeding Cold exposure Caloric deprivation Thermal neutrality  VO 2,  sympathetic activity,  heart rate,  blood pressure + - VO 2  VO 2,  sympathetic activity,  heart rate,  blood pressure

Central control of food intake Neurons responsible for the central regulation of food intake are in several areas of the hypothalamus These areas include the lateral hypothalamic area (LHA), the ventromedial hypothalamus (VMH), the arcuate nucleus (ARC), and the paraventricular hypothalamus (PVH)

Central control of food intake: VMH lesions Lesions of the VMH produce hyperphagic, obese rats – this is not due to destruction of a “satiety center,” but to an increase in autonomic tone, which leads to increased fat deposition – i.e., a new body weight “set point” – as a result of increased insulin These animals become hyperphagic in an attempt to maintain this new body weight

Lesion-Induced Weight Loss Lesions of the LH caused aphagia. Dual Center hypothesis: VMH - satiety center; LH - hunger center. Not due to hunger center, but to akinesia and sensory neglect; resemble Parkinson’s disease

Neuropeptides & control of food intake Two major classes –Anabolic Increased eating Decreased energy expenditure Increased body fat –Catabolic Reduced food intake Increased energy expenditure Loss of body fat

Central control of food intake: Signaling pathways Arcuate neurons NPY: neuropeptide Y – increased food intake AgRP: agouti-related protein – increased food intake POMC: proopiomelanocortin – precursor of  -MSH  -MSH:  -melanocyte-stimulating hormone – decreased food intake CART: cocaine-amphetamine-related transcript – decreased food intake PVN or LHA neurons MCH: melanin-concentrating hormone – increased food intake Orexin (hypocretin): also involved in sleep – increased food intake CRH: corticotropin-releasing hormone – decreased food intake Oxytocin: also involved in uterine contraction and milk letdown – decreased food intake

Catabolic pathway Alpha-MSH & CART –Activated by leptin & insulin –ICV-3rd = decrease food intake, increase energy expenditure, weight loss –Bind to melanocortin receptors (MC3 & MC4) in PVN, VMH, LH –No MC3, obese without overeating –No MC4, obese with overeating

Anabolic pathway NPY & AgRP –Inhibited by leptin & insulin –ICV-3rd = increase food intake, decrease energy expenditure, weight gain –NPY neurons to PVN (NPY receptors); NPY in PVN increase food intake –AgRP = antagonist of MC3 & MC4 receptors –AgRP to 3V, increase food intake by blocking action of alpha-MSH on MC receptors –NPY directly stimulate anabolic pathway; AgRP antagonizes tonically active catabolic peptides

Other peptides Orexin A & MCH –Injected in brain - increase in food intake –Neurons in LH, LH lesion aphagia partially due to reduced orexin and MCH Oxytocin –CCK, gastric distension, hyperosmolality –ICV oxytocin decreases food intake CRH (stress pathway) –Icv CRH decreases food intake mediated through oxytocin axons projecting to CNS, not pituitary

Leptin and insulin inhibit NPY/AgRP neurons and stimulate POMC/CART neurons – increased leptin and insulin lead to decreased food intake Central control of food intake: Arcuate nucleus

Leptin and insulin deficiency activates NPY/AgRP neurons in the arcuate n. Release of NPY and AgRP into PVN and LHA leads to increased food intake and obesity Leptin and insulin deficiency also inhibits arcuate neurons containing POMC, leading to decrease in  -MSH release and obesity AgRP inhibits melanocortin receptors Central control of food intake: Obesity

Arcuate neurons innervate second-order neurons in the PVN, PFA and LHA. CRH, TRH and oxytocin neurons in the PVN produce anorexia Orexin and MCH neurons in the PFA and LHA increase feeding Central control of food intake: Second-order neurons

Increased Leptin and insulin levels activate POMC neurons in the arcuate n. Release of POMC results in elevated  -MSH levels and decreased food intake (anorexia) At the same time leptin and insulin inhibit arcuate neurons containing NPY/AgRP, also leading to decreased food intake Central control of food intake: Anorexia

Leptin and insulin inhibit NPY/AgRP neurons and excite  -MSH/CART neurons in arcuate n. NPY/AgRP neurons inhibit PVN and excite LHA, whereas  -MSH/CART neurons stimulate PVN and inhibit LHA PVN has catabolic action, LHA has anabolic action – through connections in the brainstem (e.g., NST and area postrema) Central control of food intake: Signaling pathways Leptin and insulin

Central control of food intake: Signaling pathways Balance between satiety and adiposity signals

The End