Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways.

The increasing incidence of obesity and obesity-linked disease presents a serious global health threat. To develop truly effective therapies to modulate food intake and promote weight loss, we must understand the physiological regulators that underlie these processes. One crucial mediator of food intake and energy homeostasis is the adipose-derived hormone, leptin, which acts through neurons expressing the long form of the leptin receptor (LepRb). Although most investigation of leptin action has centered on the large population of LepRb neurons in the arcuate nucleus (ARC), this nucleus does not mediate all aspects of leptin action. Indeed, several hypothalamic and extrahypothalamic loci contain substantial numbers of LepRb neurons, each of which presumably mediates distinct aspects of leptin action, and the collective output of these various LepRb populations produces the totality of leptin function. This review will examine known central nervous system loci that contain LepRb neurons and the potential roles for discrete populations of LepRb neurons in the control of homeostatic and hedonic pathways by leptin. Understanding the unique neuroanatomical and functional roles for each locus of leptin action will be important to identify how specific aspects of food intake contribute to obesity.

LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action.

The adipose tissue-derived hormone, leptin, acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. In order to understand leptin action we have explored the physiological function of LRb signalling pathways, defining important roles for signal transducer and activator of transcription-3 (STAT3) in positive signalling and for LRbTyr(985)-mediated feedback inhibition in leptin signal attenuation. As the cells on which leptin acts are not homogeneous, but rather represent a broadly distributed network of neurones with divergent projections and functions, it is also crucial to consider how each of these populations responds to LRb signals to contribute to leptin action. While well-known LRb-expressing neurones within the arcuate nucleus of the hypothalamus mediate crucial effects on satiety and energy expenditure, other populations of LRb-expressing neurones in the ventral tegmental area and elsewhere likely control the mesolimbic dopamine system. Additional populations of LRb-expressing neurones likely contribute to other aspects of neuroendocrine regulation. It will be important to define the molecular mechanisms by which leptin acts to regulate neurophysiology in each of these LRb-expressing neural populations in order to understand the totality of leptin action.

Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma.

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (Delta Psi(M)) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by Delta Psi(M) changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining Delta Psi(M) and regulating Bcl proteins.