Summary The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone, leptin, modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA, and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system.

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

No abstract

Summary Leptin signals the repletion of fat stores, acting in the CNS to permit energy utilization by a host of autonomic and neuroendocrine processes and to decrease feeding. While much recent research has focused on the leptin-regulated circuitry of the hypothalamic arcuate nucleus (ARC), the majority of brain leptin receptor (LepRb)-expressing neurons lie outside the ARC in other brain regions known to modulate energy balance. Each set of LepRb neurons throughout the brain presumably mediates unique aspects of leptin action, and understanding the function for LepRb-expressing neurons throughout the brain represents a crucial next step in the study of energy homeostasis.

The increasing incidence of obesity in developed nations represents an ever-growing challenge to health care by promoting diabetes and other diseases. The discovery of the hormone, leptin, a decade ago has facilitated the acquisition of new knowledge regarding the regulation of energy balance. A great deal remains to be discovered regarding the molecular and anatomic actions of leptin, however. Here, we discuss the mechanisms by which leptin activates intracellular signals, the roles that these signals play in leptin action in vivo, and sites of leptin action in vivo. Using "reporter" mice, in which LRb-expressing (long form of the leptin receptor) neurons express the histological marker, ␤-galactosidase, coupled with the detection of LRb-mediated signal transducer and activator of transcription 3 signaling events, we identified LRb expression in neuronal populations both within and outside the hypothalamus. Understanding the regulation and physiological function of these myriad sites of central leptin action will be a crucial next step in the quest to understand mechanisms of leptin action and energy balance.

The adipose-derived hormone, leptin, acts via its receptor (LRb) to convey the status of body energy stores to the brain, decreasing feeding and potentiating neuroendocrine energy expenditure. The failure of high levels of leptin in most obese individuals to promote weight loss defines a state of diminished responsiveness to increased leptin, termed leptin resistance. Leptin stimulates the phosphorylation of several tyrosine residues on LRb to mediate leptin action. We homologously replaced LRb in mice with a receptor with a mutation in one of these sites (Tyr985) in order to examine its role in leptin action and signal attenuation in vivo. Mice homozygous for this mutation are neuroendocrinologically normal, but females demonstrate decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat diet-induced obesity, and increased leptin sensitivity in a sex-biased manner. Thus, leptin activates autoinhibitory signals via LRb Tyr985 to attenuate the anti-adiposity effects of leptin, especially in females, potentially contributing to leptin insensitivity in obesity. IntroductionThe prevalence of obesity continues to increase at alarming rates throughout the world, fostering the rise in obesity-related comorbidities, such as diabetes and cardiovascular disease. While body energy homeostasis is closely regulated, only recently have we begun to understand the physiologic mechanisms that regulate feeding and body weight to effect this balance. One important effector of body energy homeostasis is leptin, which is produced by adipocytes as a signal of the repletion of body energy stores. Leptin acts in the CNS to promote satiety and enable neuroendocrine energy expenditure (1-7). The lack of leptin action due to mutations in leptin (e.g., ob/ob mice) or in the active (b) form of the leptin receptor (LRb; e.g., db/db mice) or as a consequence of lowered fat stores results in increased appetite and an energy-sparing neuroendocrine starvation response that includes infertility and growth retardation (3,8). In ob/ob and db/db animals, hyperphagia paired with decreased energy expenditure results in morbid obesity and a propensity to develop type 2 diabetes. Conversely, in normal leptinsensitive animals, high leptin levels tend to reduce appetite and permit neuroendocrine energy expenditure, and leptin administration decreases feeding and body weight while preserving metabolic energy utilization. The failure of elevated leptin levels to mediate weight loss in common forms of human obesity suggests the attenuation of leptin action (leptin resistance) in obese states, as with diet-induced obesity in rodents (9-11). Potential mechanisms to explain this leptin resistance include alterations in leptin transport into the CNS and inhibition of leptin signaling (12, 13).

Leptin acts via its receptor (LepRb

Hypothalamic neurons expressing the long form of the leptin receptor (LRb) mediate important leptin actions. Although it has been suggested that leptin crosses the blood-brain barrier (BBB) via a specific transport system, we hypothesized the existence of a population of hypothalamic arcuate nucleus (ARC) neurons that senses leptin independently of this transport system. Indeed, endogenous circulating leptin results in detectable levels of baseline activated signal transducer and activator of transcription 3 (STAT3) phosphorylation in a population of ARC/LRb neurons, consistent with increased sensing of circulating leptin in these neurons compared with other LRb neurons. Furthermore, a population of ARC/LRb neurons that responds more rapidly and sensitively to circulating leptin compared with other hypothalamic LRb neurons detected by leptin activated phosphorylated STAT3. In addition, peripheral application of the BBB-impermeant retrograde tracer fluorogold revealed a population of ARC/LRb neurons that directly contact the circulation (e.g. via neuronal processes reaching outside the BBB). Taken together, these data suggest that a population of ARC/LRb neurons directly contacts the circulation and displays increased sensitivity to circulating leptin compared with neurons residing entirely behind the BBB elsewhere in the hypothalamus.