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Sci Rep. 2017 Jul 25;7(1):6355. doi: 10.1038/s41598-017-05884-y.

Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation.

Author information

1
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA.
2
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA.
3
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, 77843, USA.
4
Department of Endocrinology and the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
5
The Laboratory of Lipid & Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
6
Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58202, USA.
7
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
8
Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
9
Departments of Medical Physiology and Medicine, Texas A&M University Health Science Center, Temple, TX, 76504, USA.
10
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA. pingwei@tamu.edu.
11
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA. cdwu@tamu.edu.

Abstract

Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses. In obese mice, treatment with cGAMP significantly decreases diet-induced proinflammatory responses in liver and adipose tissues and ameliorates metabolic dysregulation. Strikingly, cGAMP exerts cell-type-specific anti-inflammatory effects on macrophages, hepatocytes, and adipocytes, which is distinct from the effect of STING activation by DMXAA on enhancing proinflammatory responses. While enhancing insulin-stimulated Akt phosphorylation in hepatocytes and adipocytes, cGAMP weakens the effects of glucagon on stimulating hepatocyte gluconeogenic enzyme expression and glucose output and blunts palmitate-induced hepatocyte fat deposition in an Akt-dependent manner. Taken together, these results suggest an essential role for cGAMP in linking innate immunity and metabolic homeostasis, indicating potential applications of cGAMP in treating obesity-associated inflammatory and metabolic diseases.

PMID:
28743914
PMCID:
PMC5526935
DOI:
10.1038/s41598-017-05884-y
[Indexed for MEDLINE]
Free PMC Article

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