Brown Adipocyte Dysfunction in UCP1 Knockout Mice leads to Age‐Dependent Development of Type 2 Diabetes

Abstract

Since the discovery of functional brown adipose tissue (BAT) in adult humans, an inverse correlation between aging, type 2 diabetes and the amount and activity of the BAT‐depots have been reported. Upon activation, BAT converts the energy of free fatty acids and glucose oxidation into heat through the mitochondrial carrier protein,uncoupling protein 1 (UCP1). BAT has recently been demonstrated to increase triglyceride uptake and insulin sensitivity. Although the thermogenic responses of UCP1 KO mice have been well studied, little is known about the short and long term effects of UCP1 deficiency and how it affects BAT function and metabolism in general.We used RNAseq to analyze and compare the BAT transcriptome of WT and UCP1 KO mice, under thermoneutral conditions at baseline and after catecholamine induced activation. The effects of aging on glucose and insulin tolerance and molecular markers of type 2 diabetes were investigated in WT and UCP1 KO mice in thermoneutrality for up to 1 year.Whole transcriptome analysis, followed by qPCR and immunoblotting, revealed marked dysfunction of key metabolic pathways in activated BAT from UCP1KO mice compared to WT mice, while at baseline thermoneutral conditions the BAT transcriptome from UCP1KO and WT mice were similar. Further, UCP1KO mice age‐dependently develop hallmarks of type 2 diabetes, such as impaired glucose tolerance and increased insulin resistance, without developing an obesity phenotype.We conclude that UCP1 KO mice are a model of severe BAT dysfunction. Long‐term BAT dysfunction is associated with age‐dependent development of hallmarks of type 2 diabetes.