Exercise training upregulates SIRT1 to attenuate inflammation and metabolic dysfunction in kidney and liver of diabetic
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RESEARCH
Open Access
Exercise training upregulates SIRT1 to attenuate inflammation and metabolic dysfunction in kidney and liver of diabetic db/db mice Hung-Wen Liu*, Hao-Han Kao and Chi-Hang Wu
Abstract Background: Chronic inflammation and metabolic dysregulation may eventually cause tissue damage in obesityrelated diseases such as type 2 diabetes. The effects of SIRT1 on integration of metabolism and inflammation may provide a therapeutic target for treatment of obesity-related diseases. We examined the underlying mechanism of moderate intensity aerobic exercise on kidney and liver in obese diabetic db/db mice, mainly focusing on inflammation and metabolic dysfunction. Methods: Functional and morphological alterations and metabolic and inflammatory signaling were examined in type 2 diabetic db/db mice with or without exercise training (5.2 m/min, 1 h/day, and 5 days/week for a total of 8 weeks). Results: Exercise training prevented weight gain in db/db + Ex mice, but it did not reduce glucose and insulin levels. Exercise lowered serum creatinine, urea, and triglyceride levels and hepatic AST and ALT activity in db/db + Ex mice. Reduced kidney size and morphological alterations including decreased glomerular cross-sectional area and hepatic macrovesicles were observed in db/db + Ex mice compared with untrained db/db mice. Mechanistically, preventing loss of SIRT1 through exercise was linked to reduced acetylation of NF-κB in kidney and liver of db/db + Ex mice. Exercise increased citrate synthase and mitochondrial complex I activity, subunits of mitochondrial complexes (I, II, and V) and PGC1α at protein level in kidney of db/db + Ex mice compared with non-exercise db/db mice. Changes in enzyme activity and subunits of mitochondrial complexes were not observed in liver among three groups. Conclusion: Exercise-induced upregulation of SIRT1 attenuates inflammation and metabolic dysfunction, thereby alleviating the progression of diabetic nephropathy and hepatic steatosis in type 2 diabetes mellitus. Keywords: Moderate exercise, SIRT1, NF-κB, Mitochondrial function, Diabetic db/db mice
Background Chronic inflammation and metabolic dysregulation may eventually cause tissue damage in metabolic diseases, particularly obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease [1]. Under pathophysiological conditions, mitochondrial dysfunction results in overproduction of mitochondrial reactive oxygen species (ROS) and further stimulates nuclear factor-kappa B (NF-κB) activity, thus leading to cellular damage and tissue dysfunction [2, 3]. Sirtuin 1 (SIRT1), a NAD+ dependent * Correspondence: [email protected] Department of Physical Education, National Taiwan Normal University, 162, Section 1, Heping E. Rd, Taipei City, Taiwan
deacetylase, functions as an energy sensor and integrates cellular metabolism and inflammation via regulating downstream signaling pathways [4]. Therefore, downregulation of SIRT1 may be one of the underlying mechanisms of disease progression [5]. Loss of SIRT1 is associated with upre
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