Abstract
Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Cyclin-dependent kinases have been shown to contribute to obesity and its adverse complications. Here, we show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at preventing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT.
Highlights
Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice
Previous studies demonstrated that roscovitine given to lean mice induced browning of white adipose tissue (WAT), enhanced energy expenditure and attenuated the weight gain from a 9-week high fat diet (HFD)[35]
We demonstrate that roscovitine is an effective anti-obesity drug that prevents weight and fat mass gain when administered to mice during the last 6 weeks of a 19-week HFD
Summary
Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. We show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Obese individuals have a high degree of fibrosis in both subcutaneous and visceral AT, with visceral fibrosis being associated with elevated serum triglycerides and limited adipocyte size, while subcutaneous fibrosis is negatively associated with weight loss after bariatric surgery[13, 14] This obesity-associated remodeling of adipose tissue accompanies an extensive decline in adipocyte mitochondrial activity that impacts major adipocyte functions such as adiponectin production[10, 15,16,17]. We document that roscovitine reduces weight gain in obese mice and prevents accompanying inflammation, fibrosis and insulin resistance
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