Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling, and is thus an attractive therapeutic target for combatting obesity. Expanding 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 metabolic tissues, including the brain and pancreatic islets. However, roles for BAT-expressed Ldb1 have not been elucidated. We set out to test the hypothesis that Ldb1 directly impacts BAT development and function. Our in vitro studies have shown that primary brown adipocytes lacking Ldb1 have reductions in BAT-selective genes including Ucp1 and Elovl3 and are unable to induce Ucp1 expression upon agonist treatment, a result similarly observed in the X9 Ucp1-expressing cell line. To test Ldb1 roles in vivo, we developed a mouse model, termed Ldb1ΔBAT, in which Ldb1 was reduced in thermogenic adipocytes using a Ucp1-driven Cre recombinase. The Ldb1ΔBAT mice were cold intolerant during a cold challenge, which is supportive of thermogenic defects in the Ldb1-deficient tissue. The knockout mice were also glucose intolerant via intraperitoneal glucose challenge and preliminary data suggest insulin insensitivity, via intraperitoneal insulin tolerance test. Histological analyses of Ldb1ΔBAT BAT depots indicated an alteration in brown adipocyte morphology and potentially intercellular lipid content, suggesting cellular dysfunction. Overall, this work indicates that Ldb1 has a direct role in maintaining thermogenic and metabolic function in BAT.
J. Kepple: None. Y. Liu: None. C.S. Hunter: None.