Thioesterase superfamily member 1 suppresses cold thermogenesis by limiting the oxidation of lipid droplet-derived fatty acids in brown adipose tissue

Abstract

ObjectiveNon-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.MethodsThem1−/− 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.ResultsThem1 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.ConclusionsThese 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.

Thioesterase Superfamily Member 1 Undergoes Stimulus-coupled Reorganization to Regulate Metabolism

“…immortalized brown adipose (iBAs) cells did not express Them1 mRNA or protein ( Supplementary Fig. 2a), as was the case for primary cultured brown adipocytes 11 . Instead, Them1 expression required transfection to study its biochemical and physiological characteristics in vitro.…”

“…Them1 was first identified as a gene that is markedly upregulated in response to cold ambient temperatures and suppressed by warm temperatures 9 . Whereas this initially suggested that Them1 function was to promote thermogenesis 9 , homozygous disruption of Them1 in mice led to increased energy expenditure 10,11 . This result indicated that Them1 functions, on balance, to suppress energy expenditure.…”

“…We next examined the role of Them1 in regulating the oxygen consumption rate (OCR) in differentiated iBAs cells in response to norepinephrine stimulation. OCR values are a surrogate measure of oxidation rates of fatty acids generated by hydrolysis of LD-derived triglycerides 11 . After optimizing conditions of cell density by calculating the total number of EGFP-containing cells/total cells per plate ( Fig.…”

Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism

“…Increased fatty acyl-CoAs in BAT and decreased thioesterase activity in BAT homogenates revealed that THEM1 functions as an ACOT in vivo [53]. The higher energy expenditure observed in Them1 −/− mice was explained by an enhanced cold thermogenesis, with THEM1 directly repressing lipolysis within BAT [54] (Figure 2). …”

“…THEM1 functions to reduce energy expenditure by limiting the oxidation of fatty acids derived from the lipolysis of lipid droplets. Adopted with permission from reference [54]. (Bottom panel) THEM2 is enriched in liver together with its interacting partner PC-TP.…”