Stein, A. G. | Search bioRxiv

bioRxiv2025

Reducing the CAV1-dependent trafficking of G6PC1 in the liver protects against the development of type 2 diabetes

Targeting hepatic gluconeogenesis is an efficient strategy to counteract the development of type 2 diabetes. Hepatic glucose production into the bloodstream is controlled by the GLUT2 transporter and a vesicular pathway dependent on Caveolin-1 (CAV1) involving G6PC1 location at the plasma membrane. We hypothesized that decreasing hepatic gluconeogenesis by targeting CAV1 specifically in the liver (L.Cav1-/- mice) improves energy and glucose metabolism in diabetic mice. Here we show that the absence of hepatic CAV1 increases insulin sensitivity, glucose tolerance and decreases fasting hyperglycemia and hyperinsulinemia in mice feeding a high fat high sucrose diet (HFHS diet). The decrease in insulin sensitivity takes place also in L.Cav1-/- mice feeding a standard diet (STD diet). Moreover, we demonstrated an improvement of glycemic control when hepatic Cav1 is deleted in previously prediabetic mice. In parallel, the absence of CAV1 in the liver reduces body weight gain and lipid intestinal absorption. Together these findings highlight that the vesicular pathway of glucose production represents a promising therapeutic target in the prevention of type 2 diabetes.

physiology↗

bioRxiv2022

Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice

Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3-signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT. Significance StatementThyroid hormones (TH) increase energy expenditure by regulating the expression of target genes in many metabolic tissues. Among them, brown adipose tissue (BAT) dissipates biochemical energy into heat production to notably prevent hypothermia during cold exposure. Hypothyroid mice display inefficient BAT thermogenesis suggesting that TH are crucial for this process. Here, we eliminated TH signaling specifically in brown adipocytes and expose the mice to different physiological stressors. We showed that TH signaling is crucial for BAT thermogenesis as it controls the expression of genes involved in proliferation and in the metabolism of lipids and glucose, the main energy resources for BAT thermogenesis. This study provides an unprecedented view on the pathways by which T3 activates energy expenditure the BAT.

genomics↗