Abstract
Interscapular brown adipose tissue (BAT) has the capability to take up glucose from the circulation. Despite the important role of BAT in the control of glucose homeostasis, the metabolic fate and function of glucose in BAT remain elusive as there is clear dissociation between glucose uptake and BAT thermogenesis. Interestingly, intracellular glycolysis and lactate production appear to be required for glucose uptake by BAT. Here, we specifically examine whether activation of lactate receptors in BAT plays a key role in regulating glucose homeostasis in mice fed a high-fat diet (HFD). When C57BL/6J mice are given HFD for 5 weeks at 28°C, male, but not female, mice gain body weight and develop hyperglycemia. Importantly, high-fat feeding upregulates expression of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) in female C57BL/6J mice, whereas male C57BL/6J mice show reduced HCAR1 expression in BAT. Treatment with the HCAR1 agonist lowers systemic glucose levels in male DIO mice. This reduction is associated with increased glucose uptake in BAT. Therefore, our results suggest that HCAR1 in BAT may contribute to the development of hyperglycemia in male C57BL/6J DIO mice.
Highlights
Interscapular brown adipose tissue (BAT) is a principal site of nonshivering thermogenesis, which results from the uncoupling of mitochondrial oxidative respiration from ATP production to generate heat [1,2,3]
We recently showed that inhibition of LDHA blocked the ability of BAT to take up glucose [10], suggesting that lactate production in BAT is necessary for glucose uptake
There were no significant differences in body weight and blood glucose levels between female mice fed LFD and those on high-fat diet (HFD) (Fig 1D and 1E), consistent with prior studies showing that male C57BL/6J mice are more likely to develop DIO and hyperglycemia than female mice [25,26,27,28]
Summary
Interscapular brown adipose tissue (BAT) is a principal site of nonshivering thermogenesis, which results from the uncoupling of mitochondrial oxidative respiration from ATP production to generate heat [1,2,3]. This uncoupling protein 1 (UCP1)-dependent thermogenesis is largely fueled by fatty acids from intracellular triglycerides in rodents and humans [4,5,6]. We recently demonstrate that optogenetic activation of sympathetic nerves exclusively innervating BAT promotes glucose uptake, resulting in a rapid reduction in blood glucose levels [10].
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