Defective brown adipose tissue thermogenesis and impaired glucose metabolism in mice lacking Letmd1

Manipulation of energy-dissipating adipocytes has the potential to produce metabolic benefits. To this end, it is valuable to understand the mechanisms controlling the generation and function of thermogenic fat. Here, we identify Letm1 domain containing 1 (Letmd1) as a regulator of brown fat formation and function. The expression of Letmd1 is induced in brown fat by cold exposure and by β-adrenergic activation. Letmd1-deficient mice exhibit severe cold intolerance concomitant with abnormal brown fat morphology, reduced thermogenic gene expression, and low mitochondrial content. The null mice exhibit impaired β3-adrenoreceptor-dependent thermogenesis and are prone to diet-induced obesity and defective glucose disposal. Letmd1 was previously described as a mitochondrial protein, and we find that it also localizes to the nucleus and interacts with the transcriptional coregulator and chromatin remodeler Brg1/Smarca4, thus providing a way to impact thermogenic gene expression. Our study uncovers a role for Letmd1 as a key regulatory component of adaptive thermogenesis. [Display omitted] •Letmd1 is a brown-fat-enriched protein induced by cold and β-adrenergic signaling•β3-adrenoreceptor-dependent energy expenditure in mice requires Letmd1•Letmd1 loss causes abnormal brown fat mitochondria and thermogenic gene expression•Letmd1 interacts with the chromatin remodeler BRG1 to regulate thermogenic genes Choi et al. report that Letmd1 deficiency in mice abolishes β3-adrenoreceptor-dependent energy expenditure and impairs systemic glucose metabolism. Because the expression of Letmd1 correlates with adipocyte thermogenesis, these findings suggest that Letmd1 is a regulatory component of the physiological thermogenic response.