Appetite Regulation, Obesity & Metabolic Syndrome

Hypothalamic control of appetite

Arcuate nucleus. Two first-order neuron populations sit beside the median eminence, where circulating signals reach them. POMC/CART neurons cleave POMC into α-MSH, which activates melanocortin-4 receptors (MC4R) in the paraventricular nucleus to produce satiety and raise energy expenditure. NPY/AgRP neurons oppose them: NPY is orexigenic, AgRP antagonizes MC4R, and their GABA output silences POMC cells. Leptin and insulin excite POMC neurons and inhibit NPY/AgRP neurons; ghrelin excites NPY/AgRP neurons.

Hunger and satiety centers. The lateral hypothalamus, home of orexin and melanin-concentrating hormone (MCH) neurons, drives feeding; bilateral destruction causes aphagia and weight loss. The ventromedial hypothalamus mediates satiety; damage from a craniopharyngioma or its surgery or radiation causes hyperphagia and hypothalamic obesity.

Memory aid: Lateral = "Let's eat"; VentroMedial = "Very Much full."

Peripheral signals

Leptin. Adipocytes secrete leptin in proportion to fat mass. Acting through its receptor and JAK2/STAT3, it activates POMC and inhibits NPY/AgRP neurons, lowering appetite and raising energy expenditure. Common obesity features high leptin with hypothalamic leptin resistance, so leptin therapy does not help. Leptin is also permissive for reproduction: low leptin in anorexia nervosa or elite athletes suppresses GnRH pulses and causes hypothalamic amenorrhea.

Ghrelin. Made mainly in the gastric fundus, ghrelin rises before meals and falls after eating. It activates NPY/AgRP neurons and the GH secretagogue receptor. Levels rise with sleep deprivation (which also lowers leptin), after diet-induced weight loss and markedly in Prader-Willi syndrome; sleeve gastrectomy removes the fundus and lowers ghrelin.

Satiety peptides and endocannabinoids. After a meal, ileal and colonic L cells release PYY, which inhibits NPY neurons through Y2 receptors, and GLP-1, which promotes satiety, slows gastric emptying and augments glucose-dependent insulin release. Duodenal I cells release CCK, signaling satiety through vagal afferents, and insulin acts centrally as an adiposity signal. Endocannabinoids push the other way through CB1 receptors (the cannabis appetite effect); the CB1 inverse agonist rimonabant caused weight loss but was withdrawn in Europe for depression and suicidality.

Adiponectin. This adipocyte hormone activates AMPK in liver and muscle, increasing fatty-acid oxidation and insulin sensitivity and lowering hepatic glucose output; it is also anti-inflammatory and anti-atherogenic. Paradoxically, it falls with visceral obesity and type 2 diabetes, while pioglitazone (a PPAR-γ agonist) raises it.

Monogenic and syndromic obesity

MC4R deficiency. The most common monogenic obesity, usually from heterozygous, dominantly inherited loss-of-function mutations. Children have early-onset hyperphagia and severe obesity with accelerated linear growth, increased lean mass and marked hyperinsulinemia; leptin is high, appropriate to fat mass.

Rare recessive defects. Leptin deficiency causes undetectable leptin, extreme hyperphagia from infancy, hypogonadotropic hypogonadism and T-cell dysfunction, all reversed by recombinant leptin (metreleptin). Leptin-receptor deficiency looks similar, but leptin is present and replacement fails. POMC deficiency adds ACTH deficiency (neonatal hypoglycemia, cholestasis, adrenal crisis) and red hair with pale skin, because α-MSH no longer stimulates MC1R.

Syndromes. Prader-Willi syndrome brings neonatal hypotonia and poor feeding followed by hyperphagia, hypogonadism and very high ghrelin. Bardet-Biedl syndrome is a ciliopathy with obesity, retinal dystrophy, polydactyly and renal anomalies.

Metabolic syndrome and insulin resistance

Definition. Diagnose when at least three of five are present (drug treatment for a component counts):

• Waist >40 in (102 cm) in men or >35 in (88 cm) in women
• Triglycerides ≥150 mg/dL
• HDL <40 mg/dL in men or <50 mg/dL in women
• Blood pressure ≥130/85 mmHg
• Fasting glucose ≥100 mg/dL

Mechanisms. Visceral fat is lipolytic and drains into the portal vein, delivering free fatty acids that raise hepatic gluconeogenesis and VLDL output (high triglycerides, low HDL, small dense LDL) and cause steatosis. Ectopic diacylglycerol activates PKC and ceramides inhibit Akt, while TNF-α and IL-6 from adipose macrophages activate JNK and IKKβ. Serine phosphorylation of IRS-1 blunts PI3K/Akt signaling, reducing GLUT4 translocation. The pancreas compensates with hyperinsulinemia until β cells fail and type 2 diabetes appears.

Consequences of hyperinsulinemia. Insulin cross-activates IGF-1 receptors on keratinocytes and fibroblasts, producing acanthosis nigricans, velvety neck and axillary plaques whose darkness reflects hyperkeratosis and papillomatosis. With LH, it drives theca-cell androgen production and suppresses hepatic SHBG, producing PCOS. Hepatic fat causes metabolic dysfunction–associated steatotic liver disease (MASLD), which can progress to steatohepatitis (MASH), cirrhosis and hepatocellular carcinoma.

Anti-obesity pharmacology

Incretin agonists. Semaglutide (weekly GLP-1 receptor agonist, about 15% weight loss) and tirzepatide (weekly dual GIP/GLP-1 agonist, about 20%) increase satiety and slow gastric emptying. They cause nausea, vomiting, diarrhea or constipation, gallstones and pancreatitis.

GLP-1–based drugs are contraindicated with a personal or family history of medullary thyroid carcinoma or with MEN2 (rodent C-cell tumors); other thyroid diseases are not contraindications.

Orlistat. It irreversibly inhibits gastric and pancreatic lipases, so about 30% of dietary fat is excreted. Expect steatorrhea, oily spotting, fecal urgency and flatus with discharge after fatty meals; reduced absorption of vitamins A, D, E and K (a bedtime multivitamin); a rising INR on warfarin from vitamin K malabsorption; and enteric hyperoxaluria with kidney stones.

Oral combinations. Phentermine is a sympathomimetic that releases norepinephrine; topiramate adds appetite suppression and carbonic anhydrase inhibition. Their effects include tachycardia, hypertension, insomnia, paresthesias, cognitive slowing, metabolic acidosis, calcium phosphate stones and teratogenicity (oral clefts), so pregnancy testing and contraception are required. In naltrexone-bupropion, bupropion stimulates POMC neurons while naltrexone blocks β-endorphin's inhibitory feedback on them; it is avoided with seizure or eating disorders, uncontrolled hypertension and chronic opioid use, and it carries an antidepressant suicidality warning.

Setmelanotide. A daily injected MC4R agonist for genetically confirmed POMC, PCSK1 or leptin-receptor deficiency and Bardet-Biedl syndrome, bypassing the broken upstream pathway. It causes skin hyperpigmentation (MC1R activation), injection-site reactions, nausea, spontaneous erections and depression.