Limiting De Novo Lipogenesis Unlocks the Thermogenic Potential of Glucose in Brown Fat

While glucose uptake is a surrogate marker of brown fat activation, its role in thermogenesis remains uncertain. To ascertain when and how glucose can fuel thermogenesis, we generated brown adipocyte-specific RalGAPB knockout (KO) mice, which have constitutively active RalA and dramatically elevated glucose uptake due to the translocation of the glucose transporter Glut4 to the plasma membrane (PM). Lean mice with RalGAPB KO showed increased lipid accumulation in brown adipocytes through elevated de novo lipogenesis (DNL) and reduced oxidative metabolism; these mice exhibited markedly reduced energy expenditure and cold tolerance. DNL inhibitors rescued the defective oxidation and energy expenditure in the KO mice. Surprisingly, brown adipocyte DNL was not increased in obese RalGAPKO mice, but energy expenditure was. Moreover, obese KO mice lost more fat than controls during fasting, due to a combination of increased energy expenditure and reduced insulin levels that favored systemic lipid oxidation. RalA was activated in brown fat by β adrenergic stimulation due to increased insulin secretion, an effect that was required for cold tolerance. This process was repressed in obesity. Together, these findings reveal that increasing glucose uptake drives energy expenditure when DNL is restricted, underscoring the context-dependent role of glucose metabolism in brown fat thermogenesis.