As to why muscle IRS-1/PI3K is downregulated in obesity will be discussed below in greater detail, but we recently found in early phases of experimental obesity induced by high fat feeding, that an abnormality in hepatic glucose production appears to be more primary than, and seems to account for, impairments in insulin signaling in muscle. This evidence concerns the gene IRS1 and obesity due to melanocortin 4 receptor deficiency.