Assessing the Interrelationship Between Adipose Tissue Thermogenesis and Fibrosis in the Metabolic Health of People Living with HIV - PROJECT SUMMARY/ABSTRACT Insulin resistance is a driver of type 2 diabetes (T2D). Despite viral suppression, people living with HIV (PLWH) have concerningly high rates of both insulin resistance and T2D. In determining what underlies this, we have focused on the fact that whereas obesity is a common trait in humans, T2D risk is increased by “metabolically unhealthy obesity” (MUO). Emerging observations highlight two factors promoting MUO in the general population: 1) reduced mitochondrial content and fewer mitochondria-enriched “brown/beige” adipocytes in the subcutaneous fat (SCAT) and 2) development of SCAT fibrosis. Interestingly, limiting brown/beige fat biogenesis in mice promotes SCAT fibrosis and insulin resistance, whereas increasing it remarkably blocks fibrosis and improves insulin sensitivity. With this in mind, we and others have observed that PLWH have dramatically increased SCAT fibrosis, prompting us to wonder whether PLWH also have suppressed brown/beige fact activity, and what factors dictate this. To this end, we recently identified a subset of adipogenic precursor cells (APCs) expressing signature markers (Lin–: PDGFRa+: CD81+) that control a reciprocal balance between beige fat biogenesis and SCAT fibrosis. Specifically, CD81+ APCs give rise to mitochondria-rich brown/beige adipocytes, whereas CD81 deficiency leads to both SCAT fibrosis and insulin resistance. These data highlight the intriguing possibility that CD81+ APCs in the SCAT may influence the development of MUO in PLWH. Beige/brown fat is also a metabolic sink for branched-chain amino acids (BCAAs), the circulating levels of which are linked to human insulin resistance. Activating brown/beige fat biogenesis either pharmacologically or by cold exposure clears circulating BCAAs in humans; indeed, BCAA clearance is a noninvasive indicator of brown/beige fat activity. However, BCAA catabolism has not been assessed in PLWH. We hypothesize that a reduced capacity of CD81+ APCs to maintain normal SCAT beige/brown function, reflected by both SCAT fibrosis and impaired BCAA clearance, drives insulin resistance in PLWH, and that reversing this may improve metabolic health. Leveraging an innovative cohort of PLWH and uninfected controls, including those with MUO, we propose to test this hypothesis by A) examining the extent to which loss of CD81+ APC abundance, proliferative capacity, or differentiation potential predicts SCAT fibrosis and insulin resistance in PLWH (Aim 1); and B) evaluataing BCAA catabolism, alongside cutting-ege PET-CT quantification of brown/beige fat activity, as a determinant of glucose homeostasis in PLWH (Aim 2). These studies will be coupled to aligned mechanistic studies in the HIV viral accessory protein (Vpr) transgenic mouse model, which is interestingly prone to both insulin resistance and impaired brown/beige fat thermogenic function. By validating a mechanistic index of SCAT health (CD81+ APCs, fibrosis, BCAA clearance) that predicts MUO, we may reveal ways to prolong the metabolic healthspan of PLWH.
