This suggests a differential clock-related response to diet challenges, where DIO prompts an unexpected rise in these clock proteins among IRcKOs. The elevated hypothalamic INS signaling in mutants may enhance thermogenesis and improve metabolic impairment, potentially explaining the negative energy balance and obesity protection observed in male IRcKO mice on the HFD. This evidence concerns the gene CLOCK and obesity due to melanocortin 4 receptor deficiency.