Leptin Does Not Directly Affect CNS Serotonin Neurons to Influence Appetite

Serotonin (5-HT) and leptin play important roles in the modulation of energy balance. Here we investigated mechanisms by which leptin might interact with CNS 5-HT pathways to influence appetite. Although some leptin receptor (LepRb) neurons lie close to 5-HT neurons in the dorsal raphe (DR), 5-HT neurons do not express LepRb. Indeed, while leptin hyperpolarizes some non-5-HT DR neurons, leptin does not alter the activity of DR 5-HT neurons. Furthermore, 5-HT depletion does not impair the anorectic effects of leptin. The serotonin transporter-cre allele (Sert(cre)) is expressed in 5-HT (and developmentally in some non-5-HT) neurons. While Sert(cre) promotes LepRb excision in a few LepRb neurons in the hypothalamus, it is not active in DR LepRb neurons, and neuron-specific Sert(cre)-mediated LepRb inactivation in mice does not alter body weight or adiposity. Thus, leptin does not directly influence 5-HT neurons and does not meaningfully modulate important appetite-related determinants via 5-HT neuron function

Leptin Receptor Signaling and Action in the Central Nervous System

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, β‐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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93692/1/oby.2006.310.pd

Mutliple Loci of Intra- and Extra-Hypothalamic Leptin Receptor Expression and Action in the Mouse.

The increasing incidence of obesity in developed nations represents an ever-growing challenge to health care by augmenting the collateral occurrences of diabetes, and other chronic conditions. The discovery of the satiety hormone, leptin, over a decade ago has facilitated the acquisition of new knowledge regarding the regulation of energy homeostasis. A great deal remains to be discovered regarding the specific actions of leptin at different regions within the brain, however. Our overarching goals were to develop a reliable method to detect long form leptin receptor (LepRb), to generate a comprehensive inventory of sites of LepRb-expressing cells in the brain and to characterize leptin action at two such sites. Here, we first define central sites of LepRb expression in vivo using "reporter" mice, in which LepRb- neurons express the fluorescent marker, enhanced green fluorescent protein (EGFP). We identified LepRb expression in neuronal populations both within and outside the hypothalamus and further characterized two such LepRb populations, those within the midbrain ventral tegmental area and linear raphe (VTA/RLi), and LepRb cells within the ventral premammillary nucleus of the hypothalamus (PMv). We used a novel tract tracing system combined with standard techniques to determine regions innervated exclusively by LepRb VTA, LepRb RLi or LepRb PMv neurons, thus revealing LepRb VTA neuronal projections to regions of the amygdala, LepRb RLi projections to amygdala and nucleus accumbens (NAc), and LepRb PMv projections to the preoptic area (POA). We have further shown the retrograde accumulation in LepRb PMv neurons of a trans-synaptic tracer from GnRH neurons, revealing the direct innervation of gonadotropin releasing hormone (GnRH) neurons by many LepRb PMv neurons. Additionally, we demonstrate activation of this population by leptin and opposite-sex odors. Thus, LepRb VTA/RLi neurons are well positioned to couple energy balance cues with the mesolimbic dopamine reward circuit, while LepRb PMv neurons unite metabolic and sexual odorant cues and directly innervate GnRH neurons to regulate the reproductive axis. Finally, in preliminary studies representing future analyses of the functional roles of LepRb PMv cells we delete Lepr in nitric oxide synthase-1 containing cells and observe a delay in estrus onset as well as delayedPh.D.Molecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64698/1/rleshan_1.pd

Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function

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. Introduction The 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 retardatio

Complex Regulation of Mammalian Target of Rapamycin Complex 1 in the Basomedial Hypothalamus by Leptin and Nutritional Status

The medial basal hypothalamus, including the arcuate nucleus (ARC) and the ventromedial hypothalamic nucleus (VMH), integrates signals of energy status to modulate metabolism and energy balance. Leptin and feeding regulate the mammalian target of rapamycin complex 1 (mTORC1) in the hypothalamus, and hypothalamic mTORC1 contributes to the control of feeding and energy balance. To determine the mechanisms by which leptin modulates mTORC1 in specific hypothalamic neurons, we immunohistochemically assessed the mTORC1-dependent phosphorylation of ribosomal protein S6 (pS6). In addition to confirming the modulation of ARC mTORC1 activity by acute leptin treatment, this analysis revealed the robust activation of mTORC1-dependent ARC pS6 in response to fasting and leptin deficiency in leptin receptor-expressing Agouti-related protein neurons. In contrast, fasting and leptin deficiency suppress VMH mTORC1 signaling. The appropriate regulation of ARC mTORC1 by mutant leptin receptor isoforms correlated with their ability to suppress the activity of Agouti-related protein neurons, suggesting the potential stimulation of mTORC1 by the neuronal activity. Indeed, fasting- and leptin deficiency-induced pS6-immunoreactivity (IR) extensively colocalized with c-Fos-IR in ARC and VMH neurons. Furthermore, ghrelin, which activates orexigenic ARC neurons, increased ARC mTORC1 activity and induced colocalized pS6- and c-Fos-IR. Thus, neuronal activity promotes mTORC1/pS6 in response to signals of energy deficit. In contrast, insulin, which activates mTORC1 via the phosphatidylinositol 3-kinase pathway, increased ARC and VMH pS6-IR in the absence of neuronal activation. The regulation of mTORC1 in the basomedial hypothalamus thus varies by cell and stimulus type, as opposed to responding in a uniform manner to nutritional and hormonal perturbations

Leptin Signaling Modulates the Activity of Urocortin 1 Neurons in the Mouse Nonpreganglionic Edinger-Westphal Nucleus

Leptin directly modulates the activity of midbrain LepRb expressing urocortin 1 neurons by recruiting JAK-STAT signaling mediated by STAT3 phosphorylation