Lect 10-17-23 (Feeding) PDF

Central Control of Feeding Fernando Gomez-Pinilla, Ph.D. Lecture # 5, 10/18/23; C144/244 F. Gomez-Pinilla, C144/244; UCLA Neural Control of Feeding • Two views on the purpose of eating: Ø To restore energy reserves (“depletion-repletion”). Hunger promotes necessity to eat. Ø To maintain caloric h...

Central Control of Feeding Fernando Gomez-Pinilla, Ph.D. Lecture # 5, 10/18/23; C144/244 F. Gomez-Pinilla, C144/244; UCLA Neural Control of Feeding • Two views on the purpose of eating: Ø To restore energy reserves (“depletion-repletion”). Hunger promotes necessity to eat. Ø To maintain caloric homeostasis. Animals primed to eat until meals generate inhibitory signals (obesity is uncommon in the wild). Caloric homeostasis • Caloric homeostasis preserves cellular metabolism. • The higher the cellular activity, the greater the demand for energy. • Most cells have limited energy storage. • Caloric homeostasis has a critical role in maintaining brain function. Ø Brain function requires sufficient blood glucose. Ø If glucose supply is compromised, neurons cease to function – loss of consciousness. Cell bioenergetics is a major factor for short- and long-term brain/ body function Diabetes Obesity Fontana, Science, 2010 Top 10 leading causes of death in US, 2010 Heart disease Cancer Respiratory diseases Stroke Accidents Alzheimer’s disease Diabetes Kidney Diseases Influenza & pneumonia Suicides Types of nutrients • • • • Three categories of nutrients: Carbohydrates --glycogen Lipids -- triglyceride Proteins -- cell structure. They can transform into carbohydrates and lipids under demand. • Storage capacity of nutrients ensures constant supply of energy Two metabolic states according to nutrients contents in circulation • Prandial or fed state, abundance of nutrients in blood. Newly ingested nutrients are used immediately or stored as glycogen (glycogenesis), or fat as triglycerides (lipogenesis). • Fasting or postabsorptive state, absence of calories entering circulation. Energy is released from stored nutrients. Storage Vs utilization of foods • Prandial period (fed state; food energy used immediately or stored as glycogen or triglycerides): • Lipogenesis, carbohydrates to lipids (also in adipose tissue) • Glycogenesis, glycogen is stored in many tissues (high in liver and skeletal muscle) • Fasting (postabsorptive) period: • Glycogenolysis, glycogen to glucose • Lipolysis, triglycerides to fatty acids and glycerol (in adipose tissue) • Gluconeogenesis, glycerol to glucose • Ketogenesis, fatty acids to ketone bodies Neural and hormonal signals regulate food intake Insulin key regulator of food intake and caloric homeostasis • Insulin is secreted by B cells in pancreatic islets. It promotes storage and efficient use of ingested nutrients • Pancreatic insulin secretion is stimulated by: • Glucose: insulin secretion is proportional to glucose concentration in pancreas. • Aminoacids and ketone bodies • ANS innervation of pancreas: • Parasympathetic: cholinergic (+) • Sympathetic: a-adrenergic (-) Meal-related insulin secretion phases • Cephalic phase: neural anticipation. Cerebral cortex -hypothalamus-- dorsal nucleus of vagus (brainstem)-- pancreas • Gastrointestinal phase: food reaching stomach or duodenum triggers GI hormones that stimulate insulin. • Substrate phase: nutrients absorbed by intestine signal pancreas via circulation. It lasts beyond stop eating. • **Rapid and well-balanced processes insulin plays a critical role on control of metabolism • High insulin promotes fuel storage. • Low insulin (low PNS or high SNS activity) promotes fuel mobilization (postabsorptive period) • Body fat: Ø Lean people compensate by having more insulin receptors in adipose tissue and sk. Muscle (reduce insulin secretion). Ø Obese – few insulin receptors. Insulin reduces appetite by acting on the hypothalamus § Insulin and leptin signal the arcuate n. resulting in less food intake. This results in release of peptides by the hypothalamus § Arcuate nucleus in the hypothalamus has chemosensors that detect signals from adipose tissue (leptin), and food intake, and regulates body weight. Insulin disorders v Insulin deficiency (pancreas dysfunction) precludes fuel storage (lean, diabetes type I). diabetes mellitus, high blood sugar v Insulin resistance due to receptor problem (fat, diabetes type II), in spite of high insulin (slow secretion). Multiple signals involved in regulation of food intake or appetite Experiments in mice show that gastric distension limits food intake Gastric distention works as a satiety signal • Gastric volume and distension: Stretch receptors in the stomach wall inform the nucleus of the solitary tract (NST) and area postrema in the brain stem via vagus nerve. • NST also communicates with hypothalamus and cerebral cortex to process gastric distension signals. Psychological: food smell, taste, texture also influence satiety/appetite Detection of calories after a meal (liver, pancreas, hypothalamus) resulting in satiety Liver- critical role in caloric homeostasis – provides satiety signal. • Increased plasma osmolality detected by liver osmoreceptors Ø Infusion of glucose or lipids into hepatic portal vein ---- food intake • Pancreas: More insulin is secreted in response to glucose infusion into stomach than into vein (intravenous)---reduction in food intake. Ø Insulin contributes to the satiety. Ø Rats made diabetic by destruction of pancreatic B cells ----- experience less postprandrial satiety. • Satiety signals inform the Ventromedial hypothalamus (VMH). Hunger emerges when satiety signals disappear!!! Meals also use chemical satiety signals • Cholecystokinin (CCK): Ø released by intestine during meals acts on stomach vagal receptors informing the brainstem. Ø Slows the rate of gastric emptying--> prolongs gastric distention à hunger suppression. Ø Acts synergistically with gastric distention. • Insulin: Ø Insulin may also act as satiety factor by reaching the brain and binding to hypothalamic receptors. Ø Insulin also reduces food intake. • Leptin satiety signal Ø Adipose tissue can release humoral factors such as hormone leptin. Ø Regulates food intake and body weight – controls satiety. Ø ob/ob mice lack leptin gene- hyperphagic & obese. Ø db/db mice lack leptin receptors. Ø Fat stores --- leptin secretion ---inhibition of food intake --- body fat loss. • Hunger signals start at post absorptive state • Ghrelin acts as a hunger hormone: Ø Released from ghrelin cells of the stomach. Ø Ghrelin levels increase during post-absorptive or fasting period. Ø Facilitates hunger resulting in meal consumption. Ø Food intake causes a decline in ghrelin secretion. Obesity as a modern epidemic Obese individuals have insulin and leptin resistance: high release but ineffective because of receptor deficiency. Body mass index (BMI)= weight (Kg)/height (m) Normal BMI: 18.5-24.9; 25-29.9 overweight; >30: obese Abdominal fat is more vascularized and active, and poses high health risk for inflammation. Obese: waist circumference >102 cm in men, >88 cm women Increased incidence of obesity in last decade • Increased consumption of calories and/or reduced physical activity Hypothalamus- brainstem main control of food intake • • NST and area postrema integrate sensory (taste) and viscera information. It receives sensory fibers from gustatory receptors (mouth, throat), stomach, intestine, pancreas, and liver. NST sends projections to hypothalamus, limbic system, thalamus and gustatory centers. • Hypothalamic connections with cerebral cortex and hippocampus provide the emotional and learning component of feeding: • Hypothalamus (VMH and VLH) and limbic system integrate taste, memory, emotion, environment. Hypothalamus together with other regions involved in feeding control • Dual center hypothesis (very controversial): • Satiety center in VMH. Its lesion causes hyperphagia and obesity, but also reduces sympathetic tone and increases parasympathetic tone (vagal reflexes): “increases fat storage and reduces duration of satiety” Hunger center in VLH, its lesion causes aphagia (absence of eating) leading to starvation, but also reduces parasympathetic tone, decreasing gastric emptying and insulin secretion Dual center hypothesis has been refuted by the fact that lesions promote a general disruption of motor and sensorimotor integration!! In addition, there are other regions in hypothalamus and brain stem (NST, parabrachial, area postrema) involved with food intake. • • Hypothalamic Control of Feeding § Arcuate nucleus in the hypothalamus has chemosensors that detect signals from adipose tissue, and food intake, and regulates body weight; for example, § Insulin and leptin signal the arcuate n. resulting in less food intake. This results in release of peptides by the hypothalamus, such as: a-MSH:member of the a-melanocortin family ACTH: adrenocorticotrophic hormone NPY: neuropeptide Y AgRP: agouti-related protein Several peptides influence food intake • Catabolic: decreases eating and increases energy expenditure: • Oxytocin (post pituitary lobe) decreases food intake. • CRH and ACTH related to stress influence on decreasing food intake • Anabolic: increases eating and decreases energy expenditure • Orexin A • Melanin-concentrating hormone (MCH) • a-MSH (melanocyte stimulating hormone): Ø member of the a-melanocortin family. Ø a-MSH axons project from ARC to PVN. Ø Acts on melanocortin (MC) receptors: MC3 and MC4 receptors on neurons in hypothalamic paraventricular nucleus (PVN). Ø Activation of a-MSH neurons- decreased food intake. Ø Animals lacking MC3 or MC4 receptors - obese • NPY and AgRP anabolic peptide: Ø ARC NPY and AgRP neurons project to the PVN. ØNPY acts at PVN - Food intake. Energy expenditure. ØAgRP antagonizes the effect of a-MSH at MC3/MC4 in PVN ---- promotes food intake. Feeding, taste, smell, etc. contribute to emotions Microbiota: closing the gap between brain and gut Fernando Gomez-Pinilla, UCLA