M Nakata1, S Yamamoto1, T Okada2,3, D Gantulga1, H Okano4, K Ozawa2, T Yada1,5. 1. Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Japan. 2. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan. 3. Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan. 4. Department of Physiology, Keio University School of Medicine, Tokyo, Japan. 5. Department of Developmental Physiology, Division of Adaptation Development, National Institute for Physiological Sciences, Okazaki, Japan.
Abstract
BACKGROUND: Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN: Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.
BACKGROUND:Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN:Adeno-associated virus (AAV) expressing murineIL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.
Authors: Wouter J de Jonge; Esmerij P van der Zanden; Frans O The; Maarten F Bijlsma; David J van Westerloo; Roelof J Bennink; Hans-Rudolf Berthoud; Satoshi Uematsu; Shizuo Akira; Rene M van den Wijngaard; Guy E Boeckxstaens Journal: Nat Immunol Date: 2005-07-17 Impact factor: 25.606
Authors: Qian Gao; Michael J Wolfgang; Susanne Neschen; Katsutaro Morino; Tamas L Horvath; Gerald I Shulman; Xin-Yuan Fu Journal: Proc Natl Acad Sci U S A Date: 2004-03-22 Impact factor: 11.205
Authors: Eduardo R Ropelle; Marcelo B Flores; Dennys E Cintra; Guilherme Z Rocha; José R Pauli; Joseane Morari; Claudio T de Souza; Juliana C Moraes; Patrícia O Prada; Dioze Guadagnini; Rodrigo M Marin; Alexandre G Oliveira; Taize M Augusto; Hernandes F Carvalho; Lício A Velloso; Mario J A Saad; José B C Carvalheira Journal: PLoS Biol Date: 2010-08-24 Impact factor: 8.029
Authors: Kendall P Murphy; Michael A Hendley; Christopher Isely; Prakasam Annamalai; Edsel Peña; R Michael Gower Journal: ACS Appl Mater Interfaces Date: 2018-12-07 Impact factor: 9.229
Authors: Kelsey H Collins; Kristin L Lenz; Eleanor N Pollitt; Daniel Ferguson; Irina Hutson; Luke E Springer; Arin K Oestreich; Ruhang Tang; Yun-Rak Choi; Gretchen A Meyer; Steven L Teitelbaum; Christine T N Pham; Charles A Harris; Farshid Guilak Journal: Proc Natl Acad Sci U S A Date: 2021-01-05 Impact factor: 11.205