Mutations in the genes encoding single-minded 1 (Sim1) and the melanocortin receptors 4 (MC4Rs) cause severe obesity in humans. In agreement, mice with Sim1 haploinsufficiency or PVH lesion are obese. Importantly, specific genetic restoration of MC4R in Sim1 neurons reduces obesity resulted from MC4R null mice by 60-70%, demonstrating a critical role for MC4Rs in Sim1 neurons in body weight regulation. However, despite the well established importance of Sim1 neurons in both humans and rodents, our understanding of Sim1 neural pathway is still limited to the level of Sim1 neurons. Downstream of Sim1 neurons, the identity of the neurotransmitters that mediate their action is not clear. Studies have been focused on the roles of neuropeptides released from Sim1 neurons (e.g. corticotrophin-releasing hormone, thyrotrophin-releasing hormone and oxytocin). However, knockout of each of these neuropeptides produced little or limited defects in feeding or body weight, suggesting a role for additional neurotransmitters. Sim1-expressing regions contain abundant vesicular glutamate transporter 2 (Vglut2, required for presynaptic glutamate release), indicating that the majority of Sim1 neurons are glutamatergic. Upstream of Sim1 neurons, how the activity of Sim1 neuron is regulated remains largely unknown. With the exception of the melanocortin input, the function of synaptic inputs is unknown. Electrophysiological data have suggested an important role for GABAergic input to PVH Sim1 neurons. However, the physiological significance of the GABAergic input is yet to be demonstrated.
Aim 1 will test the hypothesis that glutamate release mediates the action of Sim1 neurons in body weight regulation using mice with specific loss of glutamate release from Sim1 neurons.
Aim 2 will test the hypothesis that glutamate release mediates the action of MC4Rs expressed in Sim1 neurons in body weight regulation using mice with concurrent re-expression of MC4Rs and disruption of glutamate release restricted to Sim1 neurons on MC4R null background.
Aim 3 will determine the function of GABAergic input to adult Sim1 neurons on body weight regulation using a mouse model in which only GABA-A receptors in Sim1 neurons will be sensitive to Zolpidem (a specific benzodiazepine mimicking GABA-A agonist), but those in all other brain neurons will not. GABA-A receptors in all neurons will respond normally to GABA, thus these mice will behave normally except for Zolpidem action. Effects of specific activation of GABAergic input on body weight, food intake and energy expenditure will be examined by administering Zolpidem in a temporally controlled and reversible fashion. These studies will reveal the function of glutamate release, an important downstream mediator, and GABAergic input, an important upstream regulator, of Sim1 neural pathway, thus representing a significant step in our understanding of brain neurocircuitry on body weight regulation.

Public Health Relevance

Obesity is one of the greatest and the most challenging problems in medicine and is an important risk factor for type II diabetes mellitus, hypertension, and coronary heart disease. Mutations in Sim1 gene are one of important monogenic causes of obesity in both humans and rodents. Our study based on rodent models will reveal Sim1 neural pathway in body weight regulation, thus providing a framework for using Sim1 neural pathway as a therapeutic target against the current obesity epidemic.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Hyde, James F
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University of Texas Health Science Center Houston
Schools of Medicine
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Mangieri, Leandra R; Lu, Yungang; Xu, Yuanzhong et al. (2018) A neural basis for antagonistic control of feeding and compulsive behaviors. Nat Commun 9:52
Xu, Yuanzhong; Lu, Yungang; Xu, Pingwen et al. (2017) VMAT2-Mediated Neurotransmission from Midbrain Leptin Receptor Neurons in Feeding Regulation. eNeuro 4:
Xu, Pingwen; He, Yanlin; Cao, Xuehong et al. (2017) Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice. Biol Psychiatry 81:737-747
Kim, Eun Ran; Fan, Shengjie; Akhmedov, Dmitry et al. (2017) Red blood cell ?-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply. JCI Insight 2:
Cassidy, Ryan Michael; Tong, Qingchun (2017) Hunger and Satiety Gauge Reward Sensitivity. Front Endocrinol (Lausanne) 8:104
Xu, Pingwen; Zhu, Liangru; Saito, Kenji et al. (2017) Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction. Metabolism 70:152-159
Xu, Yuanzhong; Chang, Jeffrey T; Myers Jr, Martin G et al. (2016) Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release. Diabetes 65:1040-9
Fan, Shengjie; Dakshinamoorthy, Janani; Kim, Eun Ran et al. (2016) An Indirect Action Contributes to C-Fos Induction in Paraventricular Hypothalamic Nucleus by Neuropeptide Y. Sci Rep 6:19980
Yan, Chunling; He, Yanlin; Xu, Yuanzhong et al. (2016) Apolipoprotein A-IV Inhibits AgRP/NPY Neurons and Activates Pro-Opiomelanocortin Neurons in the Arcuate Nucleus. Neuroendocrinology 103:476-488
Hu, Yaohua; Robichaux 3rd, William G; Mei, Fang C et al. (2016) Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue. Mol Cell Biol 36:2440-50

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