Objective: Non-shivering thermogenesis in brown adipose tissue (BAT) plays a central role in energy homeostasis. Thioesterase superfamily member 1 (Them1), a BAT-enriched long chain fatty acyl-CoA thioesterase, is upregulated by cold and downregulated by warm ambient temperatures. Them1 (-/-) mice exhibit increased energy expenditure and resistance to diet-induced obesity and diabetes, but the mechanistic contribution of Them1 to the regulation of cold thermogenesis remains unknown.
Methods: Them1 (-/-) and Them1 (+/+) mice were subjected to continuous metabolic monitoring to quantify the effects of ambient temperatures ranging from thermoneutrality (30 °C) to cold (4 °C) on energy expenditure, core body temperature, physical activity and food intake. The effects of Them1 expression on O2 consumption rates, thermogenic gene expression and lipolytic protein activation were determined ex vivo in BAT and in primary brown adipocytes.
Results: Them1 suppressed thermogenesis in mice even in the setting of ongoing cold exposure. Without affecting thermogenic gene transcription, Them1 reduced O2 consumption rates in both isolated BAT and primary brown adipocytes. This was attributable to decreased mitochondrial oxidation of endogenous but not exogenous fatty acids.
Conclusions: These results show that Them1 may act as a break on uncontrolled heat production and limit the extent of energy expenditure. Pharmacologic inhibition of Them1 could provide a targeted strategy for the management of metabolic disorders via activation of brown fat.
Keywords: ASM, acid soluble metabolites; AUC, area under the curve; Acot, acyl-CoA thioesterase; Acyl-CoA thioesterase; Ascl, long chain acyl-CoA synthetase; Atgl, adipose triglyceride lipase; BAT, brown adipose tissue; BFIT, brown fat inducible thioesterase; CPT, carnitine palmitoyl transferase; Energy expenditure; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; FFA, free fatty acids; Fabp, fatty acid binding protein; Fatty acyl-CoA; Hsl, hormone sensitive lipase; MOI, multiplicity of infection; Mitochondria; NE, norepinephrine; OCR, oxygen consumption rate; Obesity; PKC, protein kinase C; Plin, perilipin; Ppar, peroxisome proliferator-activated receptor; RER, respiratory exchange rate; START, steroidogenic acute regulatory protein-related lipid transfer; Them1, thioesterase superfamily member; UCP, uncoupling protein; WAT, white adipose tissue.