Wired for Weight Control

Abstract

Leptin is a fat-derived hormone that plays a key role in regulating body weight. Surprising results from two independent research groups may force revision of current models of when and how leptin exerts its effects on body weight (see the Perspective by Elmquist and Flier). During a restricted period in neonates, Bouret et al. show that leptin functions as a neurotrophic factor by directing the formation of neural projection pathways in the arcuate nucleus of the hypothalamus (ARH). Later in life, leptin targets these same pathways to regulate food intake and energy balance. Pinto et al. find that adult mice deficient in leptin differ significantly from wild-type mice in the number of excitatory and inhibitory synapses in the ARH. Single-dose administration of leptin to the mutant mice induces rapid rewiring of the synaptic connections so that they more closely resemble those seen in wild-type mice. Another paper shows that signals from leptin and other hormones in the adult brain are mediated by the adenosine monophosphate (AMP)-dependent protein kinase (AMPK). Treatment of animals with leptin or insulin or by feeding decreased activity of AMPK in various regions of the hypothalamus. Expression of a dominant-negative form of AMPK in the hypothalamus reduced food intake and led to weight loss. Effects of leptin to reduce food intake and body weight appeared to require inhibition of AMPK because expression of a constitutively active AMPK blocked leptin's actions. AMPK is a critical regulator of metabolism that senses energy reserves by responding to the cellular ratio of AMP to adenosine triphosphate. The new results suggest that the same enzyme is also central to systemic hormonal regulation of food intake. J. K. Elmquist, J. S. Flier, The fat-brain axis enters a new dimension. Science 304 , 63-64 (2004). [Abstract] [Full Text] S. G. Bouret, S. J. Draper, R. B. Simerly, Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304 , 108-110 (2004). [Abstract] [Full Text] S. Pinto, A. G. Roseberry, H. Liu, S. Diano, M. Shanabrough, X. Cai, J. M. Friedman, T. L. Horvath, Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304 , 110-115 (2004). [Abstract] [Full Text] Y. Minokoshi, T. Alquier, N. Furukawa, Y.-B. Kim, A. Lee, B. Xue, J. Mu, F. Foufelle, P. Ferré, M. J. Birnbaum, B. J. Stuck, B. B. Kahn, AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428 , 569-574 (2004). [Online Journal]