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      Leptin-inhibited PBN neurons enhance counter-regulatory responses to hypoglycemia in negative energy balance

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          Abstract

          Hypoglycemia initiates the counter regulatory response (CRR), in which the sympathetic nervous system, glucagon, and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin restrains energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here, we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates leptin receptor (LepRb) and cholecystokinin (CCK)-expressing neurons of the parabrachial nucleus (PBN), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells and Cck cre -mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, while their activation mimics the CRR in a CCK-dependent manner. PBN LepRb CCK neurons represent a crucial component of the CRR system, and may represent a therapeutic target in hypoglycemia.

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          Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance.

          Gina M. Leinninger, Darren M. Opland, Young-Hwan Jo … (2011)
          Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRb(Nts) neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRb(Nts) neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRb(Nts) neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Insulin signaling in alpha cells modulates glucagon secretion in vivo.

            Dan Kawamori, Amarnath J. Kurpad, Jiang Hu … (2009)
            Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In this study, we created and characterized alpha cell-specific insulin receptor knockout (alphaIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alphaIRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alphaIRKO mice. The mutants also exhibited an age-dependent increase in beta cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normo- and hypoglycemic conditions.
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              Sixteen years and counting: an update on leptin in energy balance.

              Laurent Gautron, Joel Elmquist (2011)
              Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9809671
                Journal ID (pubmed-jr-id): 21092
                Journal ID (nlm-ta): Nat Neurosci
                Journal ID (iso-abbrev): Nat. Neurosci.
                Title: Nature neuroscience
                ISSN (Print): 1097-6256
                ISSN (Electronic): 1546-1726
                Publication date Nihms-submitted: 14 October 2014
                Publication date (Electronic): 10 November 2014
                Publication date (Print): December 2014
                Publication date PMC-release: 01 June 2015
                Volume: 17
                Issue: 12
                Pages: 1744-1750
                Affiliations
                [1 ]Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
                [2 ]Center for Integrative Physiology, University of Edinburgh, Edinburgh, UK
                [3 ]Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, and Department of Pharmacology, University of Cambridge, Cambridge, UK
                [4 ]Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
                [5 ]Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
                [6 ]Department of Chemistry, University of Michigan, Ann Arbor, MI, USA
                [7 ]Kovler Diabetes Center, University of Chicago, Chicago, IL, USA
                [8 ]Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA
                Author notes
                [9 ]Correspondence: Martin G Myers, Jr., MD, PhD, Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, 1000 Wall St; 6317 Brehm Tower, Ann Arbor, MI 48105, Phone: 734-647-9515, Fax: 734-232-8175, mgmyers@ 123456umich.edu ; Lora K. Heisler, PhD, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK AB21 9SB, Tel: 01224 437446, Fax: 01224 437300, lora.heisler@ 123456abdn.ac.uk

                Author contributions: JNF and CMP produced the data in Figs. 1- 5 and Supplemental Figs. 1- 10, with the exception of the data in Figures 1e-I (produced by PBG and LS) and measurements of catecholamines, which were performed by PM, J-MTW and RTK. MG and MR helped produce Supplemental Figs 2, 5, and 10. JCJ aided with Figures 2- 4 and with animal genotyping and husbandry. GD’A, ASG, and LKH performed the experiments in Fig. 6. Adenoviral tracers were produced by AKS and CJR. Experimental design, interpretation, and manuscript preparation were led by MGM, LKH, JNF, CMP, ASG and DPO.

                Article
                Manuscript ID: EMS60650
                DOI: 10.1038/nn.3861
                PMC ID: 4255234
                PubMed ID: 25383904
                SO-VID: 64a5303b-9b94-459e-b659-a1ad16c37d2b
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                ScienceOpen disciplines: Neurosciences
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                ScienceOpen disciplines: Neurosciences

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