Role of HCAR1 in glucose homeostasis

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The hydrocarboxylic acid receptor 1 (HCAR1) acts as a receptor for L-lactate and is coupled to Gi/o proteins. These receptors are found in both rodents and humans and are primarily expressed in white and brown adipocytes. It has been described that activation of HCAR1 by lactate inhibits lipolysis in adipocytes of mice, rats, as well as humans. According to the IDG Development Level Summary, these are targets about which virtually nothing is known. They do not have known drug or small molecule activities and satisfy the following criteria: Pubmed score (32.51), Gene RIFs (12), and antibodies (294). This receptor is also known to be associated with breast cancer and late-onset retinal degeneration. In this pilot studies, we will produce preliminary data to address the lack of cellular and animal model data associated with HCAR1. We will specifically test the hypothesis that HCAR1 in mouse brown adipose tissue plays a critical role in the control of glucose homeostasis in diet-induced obese mice. 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. Activation of BAT promotes energy expenditure by generating heat and thus, protects against obesity and diabetes in humans. Additionally, BAT possesses great capacity for glucose uptake and metabolism. However, it appears that glucose does not contribute to BAT thermogenesis. Only a small portion of glucose taken up is used for thermogenesis in rodents. Interestingly, lactate production accounts for a large proportion of glucose uptake by BAT. We recently show that optogenetic stimulation of sympathetic nerves exclusively innervating BAT increases expression of the lactate dehydrogenase A (Ldha) gene. Importantly, lactate production appears to be required for glucose uptake by BAT. A recent human study further demonstrates substantial glucose uptake and lactate release from BAT during warm conditions, suggesting that there is an autocrine and/or paracrine release of lactate from BAT. As BAT is a primary organ that expresses lactate receptors, it is highly plausible that HCAR1 in BAT may detect, sense, and respond to changes in circulating and/ or local lactate levels and that activation of HCAR1 in BAT may control glucose uptake and consequently blood glucose levels. Our on-going studies have revealed that high-fat feeding differentially regulates HCAR1 expression in female and male mice. Sex-dependent expression of HCAR1 in BAT appears to contribute to the development of hyperglycemia in male obese animals. In fact, male C57BL/6J mice fed a high-fat diet (HFD) at thermoneutrality show diet-induced obesity (DIO) and hyperglycemia with a significant reduction in HCAR1 expression in BAT. In contrast, female C57BL/6J mice on high-fat feeding do not develop hyperglycemia. These mice exhibit increased HCAR1 expression in BAT. Our preliminary results lead us to hypothesize that HCAR1 in BAT plays a key role in regulating whole-body glucose homeostasis. Aim 1. To determine whether impaired HCAR1 signaling in BAT contributes to the development of hyperglycemia in DIO C57BL/6J mice. As glucose uptake and metabolism in BAT are significantly impaired in individuals with obesity and type 2 diabetes, our findings will improve our understanding of the effects of lactate signaling through HCAR1 on whole-body glucose disposal and lead to the discovery of new therapeutic targets for better treatment of type 2 diabetes. Additionally, data collected by this pilot project will enhance the overall goal of the IDG Program as this project has high potential to impact human health by identifying animal model phenotypes for this understudied HCAR1.