At the same time, persistent elevations in adipocyte O-GlcNAc tone as well as macrophage OGT depletion in the face of prolonged overnutrition/obesity are implicated in adipose tissue dysfunctions including a loss of nutrient sensitive lipolysis, increased inflammation, excessive lipid retention, impaired adipocyte differentiation and both local and systemic insulin resistance. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.