Neuronal PTP1B regulates body weight, adiposity and leptin action

Obesity is a major health problem and a risk factor for type 2 diabetes. Leptin, an adipocyte-secreted hormone, acts on the hypothalamus to inhibit food intake and increase energy expenditure. Most obese individuals develop hyperleptinemia and leptin resistance, limiting the therapeutic efficacy of exogenously administered leptin. Mice lacking the tyrosine phosphatase PTP1B are protected from diet-induced obesity and are hypersensitive to leptin, but the site and mechanism for these effects remain controversial. We generated tissue-specific PTP1B knockout (Ptpn1−/−) mice. Neuronal Ptpn1−/− mice have reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose PTP1B deficiency increases body weight, whereas PTP1B deletion in muscle or liver does not affect weight. Neuronal Ptpn1−/− mice are hypersensitive to leptin, despite paradoxically elevated leptin levels, and show improved glucose homeostasis. Thus, PTP1B regulates body mass and adiposity primarily through actions in the brain. Furthermore, neuronal PTP1B regulates adipocyte leptin production and probably is essential for the development of leptin resistance.

[1]  B. Lowell,et al.  Leptin Receptor Signaling in POMC Neurons Is Required for Normal Body Weight Homeostasis , 2004, Neuron.

[2]  M. Schwartz,et al.  Intracellular signalling: Key enzyme in leptin-induced anorexia , 2001, Nature.

[3]  G. Shulman,et al.  Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver , 2001, Nature.

[4]  Robert A. McGovern,et al.  Leptin Directly Activates SF1 Neurons in the VMH, and This Action by Leptin Is Required for Normal Body-Weight Homeostasis , 2006, Neuron.

[5]  H. Münzberg,et al.  Leptin receptor action and mechanisms of leptin resistance , 2005, Cellular and Molecular Life Sciences.

[6]  G. Feng,et al.  Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Flier,et al.  The Fat-Brain Axis Enters a New Dimension , 2004, Science.

[8]  S. Woods,et al.  Central nervous system control of food intake , 2000, Nature.

[9]  J. Elmquist,et al.  Rethinking the central causes of diabetes , 2003, Nature Medicine.

[10]  A. Alavi,et al.  Opportunities and Challenges , 1998, In Vitro Diagnostic Industry in China.

[11]  G. Barsh,et al.  PI3K integrates the action of insulin and leptin on hypothalamic neurons. , 2005, The Journal of clinical investigation.

[12]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[13]  D. Porte,et al.  Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. , 2005, Diabetes.

[14]  Keita Kono,et al.  Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. , 2005, Cell metabolism.

[15]  J. Flier,et al.  Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. , 1998, The Journal of clinical investigation.

[16]  M. Rossmeisl,et al.  Synergistic Gene Interactions Control the Induction of the Mitochondrial Uncoupling Protein (Ucp1) Gene in White Fat Tissue* , 2000, The Journal of Biological Chemistry.

[17]  B. Goldstein,et al.  Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases , 1998, Molecular and Cellular Biochemistry.

[18]  Gang Liu.  Protein tyrosine phosphatase 1B inhibition: opportunities and challenges. , 2003, Current medicinal chemistry.

[19]  J. Flier,et al.  Divergent Roles of SHP-2 in ERK Activation by Leptin Receptors* , 2001, The Journal of Biological Chemistry.

[20]  Young-Bum Kim,et al.  PTP1B regulates leptin signal transduction in vivo. , 2002, Developmental cell.

[21]  T. Bartness,et al.  Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[22]  C. Kahn,et al.  Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. , 2002, Developmental cell.

[23]  A. Pocai,et al.  A brain-liver circuit regulates glucose homeostasis. , 2005, Cell metabolism.

[24]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[25]  K. Narayan,et al.  Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implications. , 2004, Cardiology clinics.

[26]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[27]  M. Lazar,et al.  The current biology of resistin , 2004, Journal of internal medicine.

[28]  M. Lafontan.  Fat cells: afferent and efferent messages define new approaches to treat obesity. , 2005, Annual review of pharmacology and toxicology.

[29]  一瀬 真澄.  The hypothalamic arcuate nucleus : a key site for mediating leptin's effects on glucose homeostasis and locomotor activity , 2005 .

[30]  M. Gil-Campos,et al.  Adiponectin, the missing link in insulin resistance and obesity. , 2004, Clinical nutrition.

[31]  J. Waring,et al.  PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Birnbaum,et al.  AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus , 2004, Nature.

[33]  S. Takeda.  Central control of bone remodeling. , 2005, Biochemical and biophysical research communications.

[34]  G. Ward,et al.  Selection for growth rate, feed efficiency and body composition in mice. , 1974, Genetics.

[35]  B. Kennedy,et al.  Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. , 2002, Developmental cell.

[36]  Y. Ke,et al.  Hyperleptinemia precipitates diet-induced obesity in transgenic mice overexpressing leptin. , 2003, Endocrinology.

[37]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[38]  D. James,et al.  GLUT4 Overexpression or Deficiency in Adipocytes of Transgenic Mice Alters the Composition of GLUT4 Vesicles and the Subcellular Localization of GLUT4 and Insulin-responsive Aminopeptidase* , 2004, Journal of Biological Chemistry.

[39]  Young-Bum Kim,et al.  Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice , 2000, Molecular and Cellular Biology.

[40]  J. Auwerx,et al.  Leptin , 1998, The Lancet.

[41]  A. Kalsbeek,et al.  Selective parasympathetic innervation of subcutaneous and intra-abdominal fat--functional implications. , 2002, The Journal of clinical investigation.

[42]  L. Rossetti,et al.  Intracerebroventricular leptin regulates hepatic cholesterol metabolism. , 2004, The Biochemical journal.

[43]  John J Rossi,et al.  Approaches for the sequence-specific knockdown of mRNA , 2003, Nature Biotechnology.

[44]  Clifford B. Saper,et al.  Unraveling the central nervous system pathways underlying responses to leptin , 1998, Nature Neuroscience.

[45]  A. Kalsbeek,et al.  White Adipose Tissue: Getting Nervous , 2003, Journal of neuroendocrinology.

[46]  Alexander S. Banks,et al.  STAT3 signalling is required for leptin regulation of energy balance but not reproduction , 2003, Nature.

[47]  R. Ulrich,et al.  Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. , 2003, Diabetes.