8515 Role of Insulin Receptor in Trpv1-positive Adipocyte Progenitor Cellsin Adipocyte Differentiation and Metabolic Function

Abstract Disclosure: C. Sahin: None. H. Camara: None. F. Shamsi: None. M. Lynes: None. Y. Tseng: None. Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, is an important endocrine organ in the regulation of energy balance. Stimulating BAT activation and beiging of white adipose tissue (WAT) are new strategies to combat metabolic diseases, such as obesity and diabetes. Traditionally, thermogenic adipocytes are known to originate from mesenchymal Pdgfrα-expressing adipocyte progenitor cells (APCs). A previous study conducted by our lab identified vascular smooth muscle cells as a novel cellular origin of APCs. These cells are characterized by the expression of transient receptor potential cation channel subfamily V member 1 (Trpv1+). With cold exposure, the Trpv1+ APC-derived adipocytes are increased in BAT and WAT and differentiated into highly thermogenic adipocytes. These findings indicate that the Trpv1+-APCs may play an important role in the development of brown and beige adipocytes in response to cold. This study was designed to explore the function of the Trpv1+ APC-derived adipocytes in thermogenic adipocyte differentiation and metabolic regulation. We generated a mouse model in which insulin receptor (IR), a well-known player in adipocyte differentiation, was deleted in the Trpv1+ APCs to impair their adipogenic potential. Trpv1-Cre::mTmG::IRflox transgenic and IRwt control mice were housed at cold temperature (5°C) for 7 days. Because the lineage tracing mTmG system was included, we were able to trace the fate of Trpv1+ APCs in the presence or absence of IR. We first examined the adipogenic capacity of the IR-deficient Trpv1+ cells in BAT and WAT tissues using whole-mounted adipose tissue imaging. In control mice, approximately 30% of all mature adipocytes were derived from Trpv1+ APCs in adipose tissue in response to cold. With ablation of IR in Trpv1+ APCs, this contribution was significantly reduced in BAT (by 11.7 % in females; 6.1% in males), inguinal WAT (by 16.8% in females; 19.3% males), and perigonadal WAT (by 11.4% in females; 14.8% in males) in transgenic mice compared to control mice. These results showed that IR-deficiency in the Trpv1-expressing cells impaired their adipogenesis in both male and female mice. In contrast, thermogenic genes (e.g., Ucp1, Pparγc1a, Cox7a1) were not significantly altered in BAT and inguinal WAT of the IR-deficient Trpv1+ APCs mice. Despite the changes in the adipocyte populations, we observed that deletion of IR in Trpv1+ APCs has no impact on body weight, food intake, fat mass, glucose tolerance, and insulin sensitivity relative to control mice. Taken together, blocking the contribution of Trpv1+ APCs to the mature adipocyte population results in no metabolic changes in mice, suggesting that the other APCs, such as PdgfRα+ APCs, may potentially compensate for impaired adipogenesis in different adipose tissues. Presentation: 6/1/2024