The Ldb1 Transcriptional Coregulator Is Required for Brown Adipose Development and Function

Abstract

Brown adipose tissue (BAT) is critical for thermogenesis and glucose homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling, and is thus an attractive therapeutic target for combatting obesity. Exploiting the energy uncoupling capacity of this tissue requires a greater understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the development and function of many tissues, including the brain and pancreatic islets. However, direct roles for BAT-expressed Ldb1 have not been elucidated. We set out to test the hypothesis that Ldb1 directly impacts BAT development and function. We developed a mouse model in which Ldb1 was deleted in thermogenic adipocytes using an Uncoupling protein 1 (Ucp1)-driven Cre recombinase, termed Ldb1δBAT. These knockout mice had reductions in BAT-selective mRNAs, including Ucp1 and Elovl3, a result similarly observed in X9 beige cell lines lacking Ldb1. Ldb1δBAT mice were unable to defend body temperature during a cold challenge, suggesting thermogenic defects. We also observed glucose intolerance in Ldb1δBAT mice via intraperitoneal glucose challenge. Ldb1 deletion in preadipocytes resulted in reduced Ucp1 expression upon induction to mature adipocytes. These data suggest a direct role for Ldb1 in maintaining thermogenic and metabolic function in BAT, as well as a developmental role in preadipocytes. Additional metabolic and transcriptional profiling of the Ldb1δBAT model will interrogate the mechanisms underlying Ldb1 control of BAT function, potentially leading to novel obesity and diabetes therapeutic targets. Disclosure J. Kepple: None. Y. Liu: None. T. Kim: None. G.C. Rowe: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. C.S. Hunter: None.