The cyclin dependent kinase inhibitor Roscovitine prevents diet-induced metabolic disruption in obese mice.

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.

Shifts of Immune Cell Populations Differ in Response to Different Effectors of Beige Remodeling of Adipose Tissue.

White adipose tissue (WAT) is a dynamic tissue, which responds to environmental stimuli and dietary cues by changing its morphology and metabolic capacity. The ability of WAT to undergo a beige remodeling has become an appealing strategy to combat obesity and its comorbidities. Here, by using single-cell RNA sequencing, we provide a comprehensive atlas of the cellular dynamics during beige remodeling. We reveal drastic changes both in the overall cellular composition and transcriptional states of individual cell subtypes between Adrb3- and cold-induced beiging. Moreover, we demonstrate that cold induces a myeloid to lymphoid shift of the immune compartment compared to Adrb3 activation. Further analysis showed that, Adrb3 stimulation leads to activation of the interferon/Stat1 pathways favoring infiltration of myeloid immune cells, while repression of this pathway by cold promotes lymphoid immune cell recruitment. These findings highlight that pharmacological mimetics may not provide the same beneficial effects as physiological stimuli.