PTPRT Regulates High-Fat Diet-Induced Obesity and Insulin Resistance

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Abstract

Obesity is a risk factor for many human diseases. However, the underlying molecular causes of obesity are not well understood. Here, we report that protein tyrosine phosphatase receptor T (PTPRT) knockout mice are resistant to high-fat diet-induced obesity. Those mice avoid many deleterious side effects of high-fat diet-induced obesity, displaying improved peripheral insulin sensitivity, lower blood glucose and insulin levels. Compared to wild type littermates, PTPRT knockout mice show reduced food intake. Consistently, STAT3 phosphorylation is up-regulated in the hypothalamus of PTPRT knockout mice. These studies implicate PTPRT-modulated STAT3 signaling in the regulation of high-fat diet-induced obesity.

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High-fat diet-induced obesity in animal models.

Niloofar Hariri, Louise Thibault (2010)

Epidemiological studies have shown a positive relationship between dietary fat intake and obesity. Since rats and mice show a similar relationship, they are considered an appropriate model for studying dietary obesity. The present paper describes the history of using high-fat diets to induce obesity in animals, aims to clarify the consequences of changing the amount and type of dietary fats on weight gain, body composition and adipose tissue cellularity, and explores the contribution of genetics and sex, as well as the biochemical basis and the roles of hormones such as leptin, insulin and ghrelin in animal models of dietary obesity. The major factors that contribute to dietary obesity - hyperphagia, energy density and post-ingestive effects of the dietary fat - are discussed. Other factors that affect dietary obesity including feeding rhythmicity, social factors and stress are highlighted. Finally, we comment on the reversibility of high-fat diet-induced obesity.

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Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome.

Jason Tilan, M. Johnson, Kenneth B. Baker … (2007)

The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.

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Neuronal PTP1B regulates body weight, adiposity and leptin action.

Mirela Delibegovic, Gökhan S. Hotamisligil, Kendra K. Bence … (2006)

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.

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Author and article information

Contributors

Xiaoli Chen: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 20 June 2014

Volume: 9

Issue: 6

Electronic Location Identifier: e100783

Affiliations

[1 ]Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America

[2 ]Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America

[3 ]Department of Nutrition, Case Western Reserve University, Cleveland, Ohio, United States of America

[4 ]Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

[5 ]Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America

University of Minnesota-Twin Cities, United States of America

Author notes

* E-mail: zxw22@ 123456case.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: XF AS SD CMC ZW. Performed the experiments: XF AS YW LW YZ. Analyzed the data: XF AS SD CMC ZW. Contributed reagents/materials/analysis tools: MS. Wrote the paper: XF AS CMC ZW.

Article

Publisher ID: PONE-D-14-05187

DOI: 10.1371/journal.pone.0100783

PMC ID: 4065109

PubMed ID: 24949727

SO-VID: dca4407b-cd8c-406f-ba4b-65b8a292978e

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 February 2014

Date accepted : 28 May 2014

Page count

Pages: 9

Funding

Funding came from the National Institutes of Health R01CA127590, P50CA150964, U24 DK059630 and U24-DK76174. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PTPRT Regulates High-Fat Diet-Induced Obesity and Insulin Resistance

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Abstract

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GLUT4 biology

Most cited references 40

High-fat diet-induced obesity in animal models.

Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome.

Neuronal PTP1B regulates body weight, adiposity and leptin action.

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