The Department of Veterans Affairs is the largest single provider of medical care to people with HIV in the United States. With the advances achieved in antiretroviral therapy (ART), Veterans with HIV now survive decades. However, this success is tempered by the rising burden of obesity now affecting 78% of Veterans. Defects in adipose tissue lipid storage and regulation are hallmarks of both treated HIV and obesity, which leads to a high degree of ectopic fat infiltrating organs and tissues such as skeletal muscle. The condition of excess lipid within and around muscle, termed myosteatosis, predisposes Veterans to physical function decline, frailty, disability, and cardiometabolic diseases such as diabetes and cardiovascular disease. In our current Merit supported cohort, we found that 36% of Veterans with treated HIV have myosteatotic type obesity. Further, we found that high ectopic fat accumulation in muscle (quantified by CT imaging of skeletal muscle density) is associated with reduced mitochondrial oxidative capacity, greater inflammation, and impaired muscle glucose tolerance and insulin sensitivity. Hence the quality of muscle is just as important as the quantity of muscle. However, this important phenomenon has received little attention, especially in Veterans with HIV. Indeed, the need to target mobilizing and metabolizing skeletal muscle ectopic fat while preserving/increasing the total amount of skeletal muscle is most often overlooked and represents a major research gap and unmet clinical need. From our current Merit Award funded study, we have an established collaboration of experienced VA researchers with expertise in HIV and immunology, human nutrition and metabolism, endocrinology, radiology and imaging science, and muscle physiology. Based on our findings, we have designed a multipronged integrated intervention that combines: 1) dietary replacement of saturated with unsaturated fats; 2) coadministration of L-carnitine and omega-3 fatty acid supplementation; and 3) targeted resistance exercise training. This evidence-based intervention is designed to: a) increase lipid flux by facilitating the transfer of long-chain fatty acids into muscle mitochondria for β-oxidation; b) decrease muscle proteolysis; and c) lessen insulin resistance and inflammation. Using a randomized crossover placebo-matched trial design in a cohort of 47 Veterans who have HIV and obesity, this study will determine the effects of the multi-pronged integrated intervention on: skeletal muscle density, mitochondrial oxidative capacity, and fatty acid oxidation (Aim 1); glucose tolerance, insulin sensitivity, and inflammation (Aim 2); and cardiopulmonary exercise tolerance and physical function (Aim 3). Obesity in Veterans with treated HIV is a heterogeneous condition. Our current Merit research shows myosteatotic obesity is a distinct condition from visceral or sarcopenic obesity, affected by different clinical factors. Our findings to date provide the foundatio...