Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.     

Distribution of leptin‐sensitive cells in the postnatal and adult mouse brain

Leptin plays a pivotal role in the regulation of energy homeostasis and neuroendocrine functions, and increasing evidence indicates that leptin acts on the brain to mediate many of these effects. Recent data have also suggested that leptin influences brain development during early postnatal life. Here we examined the distribution of cells that express mRNA encoding the long form of the leptin receptor (LepRb) in postnatal and adult mouse brains by using in situ hybridization. In both adults and neonates, LepRb mRNA was largely restricted to regions known to control energy balance. Labeled cells were found in the arcuate, ventromedial, and dorsomedial nuclei of the hypothalamus as well as in the lateral hypothalamic area. Heavily labeled cells were also found in the median preoptic and ventral premammillary nuclei, two hypothalamic nuclei that are known to control reproduction. Moreover, during postnatal and adult life, clearly labeled cells were found in extrahypothalamic autonomic control sites such as the nucleus of the tractus solitarius. Importantly, this receptor can induce intracellular signaling because peripheral injection of leptin caused STAT3 phosphorylation in most sites in which LepRb mRNA was expressed. LepRb mRNA was also transiently elevated in certain regions of the postnatal mouse brain, such as the cortex, hippocampus, and laterodorsal nucleus of the thalamus. Taken together, these observations are consistent with the proposed roles of leptin in feeding and neuroendocrine regulation. They also identify regions where LepRb mRNA is expressed during early postnatal life and suggest new roles for leptin in the nervous system during development. J. Comp. Neurol. 518:459–476, 2010. © 2009 Wiley‐Liss, Inc.     

Nutritional regulation of hypothalamic leptin receptor gene expression is defective in diet-induced obesity

Leptin action in the hypothalamus plays a critical role in maintaining normal food intake and body weight. Hyperleptinaemia is associated with obesity in humans and animal models, suggesting a state of leptin resistance. Although the mechanism of leptin resistance is not clearly understood, alterations in leptin receptor (Ob-R) gene expression have been proposed as a potential mechanism mediating modifications in leptin action in obesity and during changes in nutritional status (fed/fasted). The current study examined the effects of diet-induced obesity (DIO) made by feeding rats a high fat diet for 9 weeks, and nutritional status on levels of long form (Ob-Rb) and total (Ob-Rtot) Ob-R mRNA expression in the hypothalamus. In the fed state, hypothalamic Ob-Rb mRNA and Ob-Rtot mRNA levels were similar in DIO and control standard chow fed rats (SC) despite hyperleptinaemia in DIO rats. However, although an overnight fast moderately increased hypothalamic Ob-Rb mRNA levels in SC rats, fasting did not increase Ob-Rb mRNA levels in DIO rats. To address the possibility that elevated leptin concentration in DIO rats may mediate an alteration in OB-R mRNA levels, we examined the effects of adenovirus-mediated hyperleptinaemia on Ob-R gene expression in SC rats. Despite substantially elevated plasma and cerebrospinal fluid concentrations of leptin, hypothalamic Ob-R mRNA levels were similar in both groups. In conclusion, the current study demonstrates that DIO is associated with a loss of nutritional regulation of hypothalamic Ob-R mRNA levels, and that hyperleptinaemia is not sufficient to alter Ob-R mRNA expression.     

Leptin inhibits norepinephrine efflux from the hypothalamus in vitro: role of gamma aminobutyric acid

Leptin, a hormone secreted by adipocytes, produces a number of central and neuroendocrine effects, the mechanisms behind which are not completely understood. Hypothalamic norepinephrine (NE) is involved in many of the neuroendocrine effects that are associated with leptin. Therefore, we hypothesized that leptin could affect hypothalamic NE activity to bring about its central and neuroendocrine effects. Because gamma aminobutyric acid (GABA) is known to affect the release of NE, we also tested the possibility that leptin-induced changes in NE could be mediated through GABA. The mediobasal hypothalami from adult male rats were incubated in an in vitro incubation system for four consecutive incubation periods of 60 min each at 37 degrees C in Krebs Ringers Henseleit (KRH) solution in an atmosphere of 95% O(2) and 5% CO(2.) After determining the basal release, the hypothalami were challenged with 0, 0.1, 1 or 10 nm of leptin, bicuculline (a GABA-A receptor antagonist; 10 microM) and bicuculline (10 microM) +10 nM of leptin during the second incubation period. Residual effects of leptin were measured in the third incubation where tissues were incubated with KRH alone, and the viability of tissues was determined in the fourth incubation when tissues were exposed to high K(+) KRH. NE levels in the incubation medium were measured using high-performance liquid chromatography with electrochemical detection (HPLC-EC). Leptin inhibited NE efflux from the hypothalamus in a dose-dependent manner. Moreover, incubation of hypothalami with 10 nM of leptin and bicuculline, a completely blocked the leptin-induced decrease in NE efflux. These results demonstrate for the first time that leptin could act directly on the hypothalamus to inhibit NE efflux through GABA. It was concluded that leptin could probably produce its central and neuroendocrine effects by modulating NE and GABA levels in the hypothalamus.