Regulation of Hunger
Leptin
• Since the discovery of leptin and its receptors , there has been a rapid accumulation of information about genes, peptides, other neurotransmitters, and receptors in the hypothalamus and neighboring areas that are involved in appetite regulation.
• leptin operates as part of a feedback loop by which the size of the body's fat depots can operate through a humoral link to regulate food intake
• One important factor is neuropeptide Y
• When injected into the hypothalamus, this 36-amino-acid polypeptide increases food intake, and inhibitors of neuropeptide Y synthesis decrease ood intake.
• Neuropeptide Y-containing neurons have their cell bodies in the arcuate nuclei and project to
• the paraventricular nuclei.
• Neuropeptide Y mRNA in the hypothalamus increases during feeding and decreases during satiety.
• Neuropeptide Y exerts its effect through three known receptors—Y1, Y2, and Y5—all coupled to G proteins.
• Activation of the Y5 receptor increases food intake, but the situation is complex because activation of the Y2 receptor has an apparent inhibitory effect.
• Knockout of the neuropeptide Y gene does not produce marked effects on feeding, indicating that other pathways are also involved, but knocking out the neuropeptide Y gene in leptin-deficient ob/ob mice causes them to eat less and expend more energy than ob/ob controls that have intact neuropeptide Y genes.
Orexin-A and orexin-B
• Other polypeptides that increase food intake include orexin-A and orexin-B, derived from the same gene by alternate splicing.
• They act on two receptors.
• Orexins are synthesized in neurons located in the lateral hypothalamus.
• They are also of interest because a mutation in one of the orexin receptor genes causes narcolepsy in dogs.
Melanin-concentrating hormone
• Another polypeptide that increases food intake in mammals is melanin-concentrating hormone,
• 19-amino-acid polypeptide which is secreted by the pituitary in fish and is involved in the control of their skin color .
• In mammals, its mRNA is found only in the lateral hypothalamus and the zona incerta
Pro-opiomelanocortin (POMC) derivatives
• On the other hand, pro-opiomelanocortin (POMC) derivatives decrease food intake.
• There are four established receptors for these derivatives:
• MC1-R, which is involved in skin pigmentation;
• MC2-R, which is involved in adrenal glucocorticoid production;
• MC3-R, which is associated with the control of sebaceous gland secretion; and
• MC4-R, which mediates the effects on appetite.
CART (cocaine- and amphetamine-regulated transcript)
• Another neuropeptide found in the hypothalamus that inhibits food intake is CART (cocaine- and amphetamine-regulated transcript).
CRH
• CRH, the brain hormone that stimulates ACTH secretion also inhibits food intake
Catecholamines
• Catecholamines are also involved in the regulation of body weight.
• Mice in which norepinephrine and epinephrine synthesis is prevented by knocking out the gene for dopamine b-hydroxylase have increased food intake.
• Interestingly, they do not become obese because they also have an unexplained simultaneous increase in metabolic rate.
• Amphetamine and related drugs used clinically to suppress appetite presumably act by releasing norepinephrine in the CNS.
• Mice in which the 5HT2C receptor is knocked out become obese, indicating that serotonin is also involved in the regulation of food intake.
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