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Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Departments of Medicine and Neuroscience (E.v.d.W., S.M.L., Y.H.J., G.J.S., S.C.C.), Albert Einstein College of Medicine, Bronx, New York 12461; Department of Medicine and Physiology (R.L., M.G.M.), University of Michigan Medical School, Ann Arbor, Michigan 48109; University of California, San Francisco, Diabetes Center (A.W.X.), University of California, San Francisco, San Francisco, California 94143; Department of Physiology (N.B.), University of Bristol, Bristol BS13NY, United Kingdom; Department of Internal Medicine (R.C., J.E.), Center for Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Psychiatry and Behavioral Neurosciences (R.G.M.), Wayne State University School of Medicine, Detroit, Michigan 48202; Department of Biostatistics (D.B.A.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pharmacology (N.J.D.), Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Department of Medicine (B.B.L.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; Departments of Pediatrics and Genetics (G.S.B.), Stanford University School of Medicine, Palo Alto, California 94305; and Department of Medicine (C.d.L.), University of California, San Diego, California 92161

Address all correspondence and requests for reprints to: Dr. Streamson Chua, Belfer Suite 701, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 12461. E-mail: schua{at}aecom.yu.edu.

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.

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