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

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71583/1/j.1748-1716.2007.01784.x.pd

Phosphatidylinositol 3‐kinase and Akt effectors mediate insulin‐like growth factor‐I neuroprotection in dorsal root ganglia neurons

Insulin‐like growth factor‐I (IGF‐I) protects neurons of the peripheral nervous system from apoptosis, but the underlying signaling pathways are not well understood. We studied IGF‐I mediated signaling in embryonic dorsal root ganglia (DRG) neurons. DRG neurons express IGF‐I receptors (IGF‐IR), and IGF‐I activates the phosphatidylinositol 3‐kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF‐I through the PI3K/Akt pathway. IGF‐I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein (CREB) and the pro‐apoptotic effector proteins glycogen synthase kinase‐3β (GSK‐3β) and forkhead (FKHR). IGF‐I regulates survival at the nuclear level through accumulation of phospho‐Akt in DRG neuronal nuclei, increased CREB‐mediated transcription, and nuclear exclusion of FKHR. High glucose increases expression of the pro‐apoptotic Bcl protein Bim (a transcriptional target of FKHR). However, IGF‐I does not regulate Bim or anti‐apoptotic Bcl‐xL protein expression levels, which suggests that IGF‐I neuroprotection is not through regulation of their expression. High glucose also induces loss of the initiator caspase‐9 and increases caspase‐3 cleavage, effects blocked by IGF‐I. These data suggest that IGF‐I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK‐3β, CREB, and FKHR, and by blocking caspase activation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154325/1/fsb2fj041581fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154325/2/fsb2fj041581fje-sup-0001.pd

Loss of Cytokine-STAT5 Signaling in the CNS and Pituitary Gland Alters Energy Balance and Leads to Obesity

Signal transducers and activators of transcription (STATs) are critical components of cytokine signaling pathways. STAT5A and STAT5B (STAT5), the most promiscuous members of this family, are highly expressed in specific populations of hypothalamic neurons in regions known to mediate the actions of cytokines in the regulation of energy balance. To test the hypothesis that STAT5 signaling is essential to energy homeostasis, we used Cre-mediated recombination to delete the Stat5 locus in the CNS. Mutant males and females developed severe obesity with hyperphagia, impaired thermal regulation in response to cold, hyperleptinemia and insulin resistance. Furthermore, central administration of GM-CSF mediated the nuclear accumulation of STAT5 in hypothalamic neurons and reduced food intake in control but not in mutant mice. These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF

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

IGF-I protects neurons against glucose -induced mitochondrial damage and apoptosis.

Neuropathy is the most common complication of diabetes, occurring in more than half of all diabetic patients. The disorder is pathologically characterized by degeneration of dorsal root ganglion sensory (DRG) neurons. The severity of diabetic neuropathy is linked to hyperglycemia, suggesting that high glucose levels potentiate DRG neuronal degeneration and functional loss. Thus, potential therapies must promote neuronal viability, structural integrity and regeneration. Insulin-like growth factor-I is a promising therapy in this regard because of its neurotrophic and neurotropic effects on neurons of the peripheral nervous system. The goal of this project was to identify points of IGF-I neuroprotection in DRG sensory neurons. The studies presented in this thesis use an in vitro model of diabetic neuropathy to explore the hypotheses that (1) high glucose causes mitochondrial dysfunction in neurons and activation of mitochondrial apoptotic machinery and (2) IGF-I prevents these deleterious effects. Our data suggest that IGF-1 inhibits high-glucose mediated apoptosis via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and downstream Akt effectors. Altogether, our data support a model in which high glucose treatment initiates two separate, but ultimately convergent, pathways in DRG neurons. First, high glucose causes increased expression of the pro-apoptotic BH3-only protein Bim, which induces Bax activation, cytochrome c release from mitochondria, downstream activation of caspases, and apoptotic cell death. IGF-I inhibits this pathway via sequestering Bim from mitochondria, thereby inhibiting Bax activation, mitochondrial localization, and downstream apoptotic effects. Secondly, high glucose increases expression of the mitochondrial fusion protein Drp1. The Bim/Bax pathway converges upon Drp1, and together these pathways promote aberrant mitochondrial morphology and reduced mitochondrial integrity in DRG neurons. IGF-I likely inhibits these mitochondrial deficits by suppressing activation of the Bim/Bax pathway and preventing convergence with mitochondrial fission proteins. Collectively, our results demonstrate that IGF-I mediates protection via the P13K/Akt pathway, which promotes mitochondrial integrity and prevents DRG neuronal apoptosis.Ph.D.Biological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124860/2/3163862.pd

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may, therefore, be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss and, hence, to prevent weight regain

Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that affect energy balance. Identification of which VTA DA neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet-induced weight gain. VTA NtsR1 neurons thus represent a molecularly defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity

Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction

Summary: The hypothalamus plays a crucial role in the modulation of social behavior by encoding internal states. The hypothalamic hypocretin/orexin neurons, initially identified as regulators of sleep and appetite, are important for emotional and motivated behaviors. However, their role in social behavior remains unclear. Using fiber photometry and behavioral analysis, we show here that hypocretin neurons differentially encode social discrimination based on the nature of social encounters. The optogenetic inhibition of hypocretin neuron activity or blocking of hcrt-1 receptors reduces the amount of time mice are engaged in social interaction in males but not in females. Reduced hcrt-1 receptor signaling during social interaction is associated with altered activity in the insular cortex and ventral tegmental area in males. Our data implicating hypocretin neurons as sexually dimorphic regulators within social networks have significant implications for the treatment of neuropsychiatric diseases with social dysfunction, particularly considering varying prevalence among sexes