Brain somatic cross-talk: ghrelin, leptin and ultimate challengers of obesity.
Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways.
Popovic
Vera
V
Neuroendocrine Unit, Institute of Endocrinology, University Clinical Center, Belgrade, Serbia, Yugoslavia. popver@eunet.yu
Duntas
Leonidas H
LH
D000273:Adipose Tissue; D000818:Animals; D001066:Appetite / Q000187:drug effects; D001835:Body Weight; D001921:Brain / Q000378:metabolism*; D004734:Energy Metabolism; D054439:Ghrelin; D006801:Humans; D007031:Hypothalamus; D020738:Leptin / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology* / Q000517:prevention & control; D010446:Peptide Fragments; D036361:Peptide Hormones / Q000502:physiology*; D019894:Peptide YY / Q000494:pharmacology; D010902:Pituitary Gland; D012527:Satiation / Q000187:drug effects; D015398:Signal Transduction
D054439:Ghrelin; D020738:Leptin; D010446:Peptide Fragments; D036361:Peptide Hormones; D019894:Peptide YY; C061785:peptide YY (3-36)