title: LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity.
abstract: The broadly expressed transcriptional coregulator LDB1 is essential for β-cell development and glucose homeostasis. However, it is unclear whether LDB1 has metabolic roles beyond the β-cell, especially under metabolic stress. Global Ldb1 deletion results in early embryonic lethality; thus, we used global heterozygous Ldb1+/- and inducible β-cell-specific Ldb1-deficient (Ldb1Δβ-cell) mice. We assessed glucose and insulin tolerance, body composition, feeding, and energy expenditure during high-fat diet exposure. Brown adipose tissue (BAT) biology was evaluated by thermogenic gene expression and LDB1 chromatin immunoprecipitation analysis. We found that partial loss of Ldb1 does not impair the maintenance of glucose homeostasis; rather, we observed improved insulin sensitivity in these mice. Partial loss of Ldb1 also uncovered defects in energy expenditure in lean and diet-induced obese (DIO) mice. This decreased energy expenditure during DIO was associated with significantly altered BAT gene expression, specifically Cidea, Elovl3, Cox7a1, and Dio2. Remarkably, the observed changes in energy balance during DIO were absent in Ldb1Δβ-cell mice, despite a similar reduction in plasma insulin, suggesting a role for LDB1 in BAT. Indeed, LDB1 is expressed in brown adipocytes and occupies a regulatory domain of Elovl3, a gene crucial to normal BAT function. We conclude that LDB1 regulates energy homeostasis, in part through transcriptional modulation of critical regulators in BAT function.
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Christine
authors.initials: C
authors.lastname: Loyd
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Teayoun
authors.initials: T
authors.lastname: Kim
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Cassie
authors.initials: C
authors.lastname: Holleman
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Jamie
authors.initials: J
authors.lastname: Galloway
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Maigen
authors.initials: M
authors.lastname: Bethea
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Ediger
authors.affiliation: Department of Epidemiology, School of Public Health.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Swain
authors.affiliation: Department of Medicine, Division of Cardiovascular Disease.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.|Department of Medicine, Division of Cardiovascular Disease.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Department of Medicine, Division of Cardiovascular Disease.
authors.forename: Martin
authors.initials: M
authors.lastname: Young
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Chad S
authors.initials: CS
authors.lastname: Hunter
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation; D006579:Heterozygote; D006706:Homeostasis / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C102084:Ldb1 protein, mouse