Dataset Information

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

ABSTRACT: We show that roscovitine; a cyclin-dependent kinases inhibitor; given to 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 and fibrosis. It also restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that Roscovitine induced a limited set of proteins associated with lipid metabolism, fatty acid oxidation metabolism and adipose tissue remodeling but suppressed expression of a larger array of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. Furthermore, the phosphoproteome analysis identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases [e.g., CDKs and MAPKs], AGC kinases [e.g., S6K and PKC isoforms], and CAMK kinases [e.g., SIK1 and SIK2]). Pathway enrichment analysis of annotated kinase-substrate pairs showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and phosphatidylcholine and creatine biosynthesis are enriched following roscovitine treatment. The increased creatine pathways combined with more active mitochondria in eWAT may contribute to roscovitine-induced weight loss. Surprisingly, we found that unlike for eWAT, roscovitine led to up regulation of large sets of proteins and phosphosites in brown adipose tissue (BAT). Analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups (AGC kinases [e.g., PKD1 and PKA] and CMGC kinases [e.g., CDKs and MAPKs]. Among the top enriched pathways of kinase-substrate pairs were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling, suggesting that roscovitine led to a metabolically more active BAT. Overall, roscovitine treatment led to restoration of mitochondrial activity in BAT and eWAT suppressed by HFD, likely accounting for enhanced energy expenditure and weight loss.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Adipose Tissue, Epididymal White Adipose Tissue

DISEASE(S): Obesity

SUBMITTER: Ryan Hekman

LAB HEAD: Nabil Rabhi

PROVIDER: PXD027981 | Pride | 2021-11-03

REPOSITORIES: Pride

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			Action	DRS
	20190521_RH_NCB_F10_phos.raw	Raw
	20190521_RH_NCB_F11_phos.raw	Raw
	20190521_RH_NCB_F12_phos.raw	Raw
	20190521_RH_NCB_F1_phos.raw	Raw
	20190521_RH_NCB_F2_phos.raw	Raw

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

Rabhi Nabil N Desevin Kathleen K Cortez Briana Noel BN Hekman Ryan R Lin Jean Z JZ Emili Andrew A Farmer Stephen R SR

Scientific reports 20211013 1

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 w ...[more]

PMID: 34645915

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