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Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth.

ABSTRACT: Impaired angiogenesis is a hallmark of metabolically dysfunctional adipose tissue in obesity. However, the underlying mechanisms restricting angiogenesis within this context remain ill-defined. Here, we demonstrate that induced endothelial-specific depletion of the transcription factor Forkhead Box O1 (FoxO1) in male mice led to increased vascular density in adipose tissue. Upon high-fat diet feeding, endothelial cell FoxO1-deficient mice exhibited even greater vascular remodeling in the visceral adipose depot, which was paralleled with a healthier adipose tissue expansion, higher glucose tolerance and lower fasting glycemia concomitant with enhanced lactate levels. Mechanistically, FoxO1 depletion increased endothelial proliferative and glycolytic capacities by upregulating the expression of glycolytic markers, which may account for the improvements at the tissue level ultimately impacting whole-body glucose metabolism. Altogether, these findings reveal the pivotal role of FoxO1 in controlling endothelial metabolic and angiogenic adaptations in response to high-fat diet and a contribution of the endothelium to whole-body energy homeostasis.

SUBMITTER: Rudnicki M

PROVIDER: S-EPMC6279348 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth.

Rudnicki Martina M Abdifarkosh Ghoncheh G Nwadozi Emmanuel E Ramos Sofhia V SV Makki Armin A Sepa-Kishi Diane M DM Ceddia Rolando B RB Perry Christopher Gr CG Roudier Emilie E Haas Tara L TL

eLife 20181204

Impaired angiogenesis is a hallmark of metabolically dysfunctional adipose tissue in obesity. However, the underlying mechanisms restricting angiogenesis within this context remain ill-defined. Here, we demonstrate that induced endothelial-specific depletion of the transcription factor Forkhead Box O1 (FoxO1) in male mice led to increased vascular density in adipose tissue. Upon high-fat diet feeding, endothelial cell FoxO1-deficient mice exhibited even greater vascular remodeling in the viscera ...[more]

PMID: 30511639

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Project description:Thiamine prevents diabetic complications, and its deficiency, resulting from mutation of thiamine transporter gene SLC19A2 has been linked to diabetes mellitus. We previously found that thiamine mitigates metabolic disorders in spontaneous hypertensive rats, harboring defects in glucose and fatty acid metabolism. The current study extends our hypothesis that that thiamine intervention may impact metabolic abnormalities in polyphagia-induced Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin A receptors. Male OLETF rats exhibit progressive obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4-week-old) were given free access to water containing either 0.2 % or 0 % of thiamine for 51 weeks. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, the organs were removed and weights of organs and histological findings were evaluated. In addition, differential gene expression in the liver was analyzed. Thiamine intervention averted obesity, mainly resulting from reduction of visceral adiposity, and prevented metabolic disorders in OLETF rats. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Seventy-six genes showed at least two-fold difference in hepatic expression with thiamine treatment. Several of them participated in carbohydrate metabolism (Hk1, Pygb, Slc2a8, Rtn4, Rhbdl1, and Tspan8), lipid metabolism (Pla2g15, Por, and Lmf1), vascular physiology (S1pr1, Epha8, Rtn4, Slc7a13, Cdh15, Itga9, Cd151, Cd40lg, Nid1 and Lamb1), and carcinogenesis (Lmo7, Fgfr3, and Dmbt1). Modification of transcript expression well accorded with the findings of blood parameters and organ morphologies. Thiamine prevented polyphagia-induced obesity and metabolic and functional disorders in OLETF rats.

Dataset Information

Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth.

Publications

Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth.

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