Brown and beige thermogenic adipocytes are specialized in energy consumption and linked to metabolic health. Canonically, thermogenic adipocytes are thought to be derived from mesenchymal PdgfRα+ adipocyte progenitor cells (APC) . We recently identified a novel population of cold-recruited APCs from the vascular smooth muscle lineage marked by the expression of the ion channel Trpv1 in mouse adipose tissue. To determine the function of the Trpv1+ APC-derived adipocytes, we impaired their adipogenic capacity by deletion of Pparγ in Trpv1-expressing cells in mice (Trpv1-Cre::Pparγ-flox) . Inhibition of de novo adipogenesis from Trpv1+ APCs resulted in modest changes in brown adipose tissue, but it caused a marked reduction in the expression of cold-induced browning genes, including UCP1, in white adipose tissue (WAT) , indicating impaired beige adipogenesis. Interestingly, Trpv1-Cre::Pparγ-flox mice did not show altered weight gain, glucose tolerance, or insulin sensitivity on either regular chow or high-fat diets. This discrepancy led us to search for potential compensatory mechanisms. We observed increased PdgfRα expression in WAT of Trpv1-Cre::Pparγ-flox animals, suggesting that impaired adipogenic capacity of the Trpv1+ APCs may trigger recruitment of the PdgfRα+ APCs. Additionally, while UCP1 expression was noticeably reduced in the beige adipocytes within WAT, the expression of transcripts involved in the UCP1-independent thermogenic pathways, including Ckmt1, Gatm, and Slc6a8, key components of the creatine futile cycle, was increased in the WAT of the Trpv1-Cre::Pparγ-flox mice upon cold exposure. Together, these data highlight a potential distinction between the thermogenic pathways mediated by adipocytes derived from the Trpv1+ versus those derived from the PdgfRα+ APCs. This functional difference of thermogenic adipocytes could be critical in designing strategies to target these cells as a therapeutic approach for metabolic diseases. Disclosure H.Camara: None. F.Shamsi: None. M.Lynes: None. Y.Tseng: Consultant; Cellarity. Funding National Institutes of Health (R01DK102898)
Lipids play an essential role in physiology. In addition to serving as an energy source, bioactive lipids, also known as lipokines, function as signaling molecules regulating metabolism and inflammation. A major source of lipokines, brown adipose tissue (BAT) has been shown to have beneficial effects on cardiometabolic health by increasing energy expenditure and improving glucose tolerance, thus providing a potential target for therapeutic interventions. Recent studies have identified 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME, produced by cytochrome P450-epoxide hydrolase metabolism of linoleic acid (C18:2n-6), as a lipokine produced by BAT that modulates fatty acid uptake (FAU) into brown adipocytes and skeletal muscle cells in response to cold stimulation or exercising, respectively. Here, we characterized the molecular mechanism and structure-activity relationship (SAR) of 12,13-diHOME in BAT fatty acid uptake. Conversion of the terminal carboxylic acid of 12,13-diHOME to ethyl acetate and changes in saturation results in decreased stimulated FAU indicating 12,13-diHOME's activity is structurally dependent. In addition, we provide insight into a novel protein target responsible for enhancing FAU in BAT, in part, by enhancing intracellular calcium mobilization and influencing the expression of lipolytic genes. Furthermore, we have determined that the 12,13-diHOME-stimulated FAU is, in part, dependent on Gq-mediated calcium mobilization as determined by the utilization of Gq inhibitor YM-254890. Thus, the receptor of 12,13-diHOME could represent a target to augment BAT activity by modulating fatty acid metabolism, which could contribute to increased energy expenditure and, consequently, to the prevention of cardiometabolic diseases. Disclosure J.I.Senfeld: None. M.Lynes: None. S.Kodani: None. K.Lee: None. Y.Tseng: Consultant; Cellarity, LyGenesis.
Light plays an essential role in life. Animals and humans possess light-sensing photoreceptors in visual and non-visual organs. We and others recently showed a non-visual role for Opsin3 (Opn3) in regulating adipose function. In this study, we discovered that direct blue light exposure to subcutaneous white adipose tissue (WAT) could reduce lipids accumulation in WAT and improve high-fat diet-induced metabolic abnormalities in an Opn3-dependent manner. Adipose tissue is an orchestrated matrix comprising high innervation that can engage in crosstalk with other organs. Particularly, it communicates with the brain via the sympathetic nervous system (SNS). Using the metabolomic approach, we found that blue light increased circulating levels of histidine, which then triggered the activation of histaminergic neurons in the hypothalamus and turned on brown adipose tissue via SNS. The administration of histidine decarboxylase antagonist blunted the effects of blue light. Taken together, these data demonstrate a novel light-responsive adipose-hypothalamus axis in metabolic regulation and provide a potential light-based therapeutic approach for obesity. Disclosure T.Tsuji: None. T.Huang: None. Y.Zhang: None. M.Lynes: None. G.Profeta: None. N.Narain: None. M.Kiebish: None. Y.Tseng: Consultant; Cellarity, LyGenesis. Funding American Heart Association (903968)
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