DESCRIPTION: Peripheral artery disease (PAD) affects an estimated 12 -15 million adults in the US and an estimated 20% of older Veterans. Those with PAD ambulate with slow gait and experience decreased leg strength, dysmobility, reduced quality of life, serious morbidity and often premature death. It is estimated that over 60% of individuals with PAD are overweight or obese. While PAD itself worsens mobility, obesity adds a further functional burden to older adults with PAD. Individuals diagnosed with PAD, who are also obese typically claudicate 40% more quickly than non-obese individuals and take 20% longer to recover after claudication. Studies of older obese adults without PAD have demonstrated that the combination of exercise and weight loss is more effective at improving physical function, body composition, and cardiometabolic risk factors than exercise alone. While these findings likely translate to older adults with PAD, this hypothesis has yet to be tested. This CDA-2 is designed to determine whether weight loss and exercise (WL+EX) versus exercise ( EX ) alone will 1) improve mobility function to a greater extent than exercise alone and 2) determine the mechanisms underlying changes in mobility function by measuring muscle microvascular perfusion, systemic and muscle inflammation, cardiometabolic risk, and muscle composition. We hypothesize that a combined intervention of weight loss and exercise (aerobic and resistive) will result in greater improvements in mobility function through improved muscle perfusion, reduced inflammation and reduced muscle fat infiltration than exercise alone in obese Veterans with PAD. The goals of this 5 year CDA-2 are for me to conduct a randomized controlled trial to determine the functional and underlying metabolic effects of 6 months of weight loss and exercise (WL+EX) versus exercise training alone (EX) in obese Veterans with Fontaine Stage II PAD to learn skills in the assessment of muscle perfusion, inflammation and lipid infiltration. The specific aims are: Aim 1: To compare the effects of WL+EX vs EX on mobility function in Veterans with PAD. Aim 2: To compare the effects of WL+EX vs EX on the mechanisms underlying changes in mobility function measured as muscle perfusion, inflammation and lipid infiltration. We will study 76 older (60+ years) obese Veterans with PAD. Prior to baseline testing all participants will be weight stabilized. After weight stabilization baseline testing followed by randomization will occur. Participants will undergo mobility testing (gait speed, modified physical performance test, and six minute walk distance), walking impairment questionnaires, lower extremity muscle strength testing (1RM for major lower extremity muscle groups),and measures of body composition (DXA and CT scan) and muscle perfusion (contrast enhanced ultrasonography). Muscle biopsies and blood draws will determine inflammatory levels (IL- 6 and TNF-α). All participants will participate in a gradul...