The purpose of the present study was to evaluate baseline muscle and liver insulin sensitivity and metabolic factors associated with insulin resistance (i.e., percentage body mass as fat, intra-abdominal adipose tissue volume, intrahepatic triglyceride content, adipocyte size, and specific circulating hormone, inflammatory protein, and metabolite concentrations) and the weight loss–induced changes in these metabolic variables in women with obesity who were considered metabolic Responders or Non-responders to marked (16%–25%) weight loss. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.