By employing a unique adipocyte-specific PPARγ acetylation-mimetic mutant knock-in mouse model, namely aKQ, we demonstrate that these mice develop worsened obesity, insulin resistance, dyslipidemia, and glucose intolerance as they age, and these metabolic deregulations are resistant to intervention by intermittent fasting. The gene discussed is PPARG; the disease is obesity due to melanocortin 4 receptor deficiency.