Lipodystrophy and obesity represent extreme and opposite ends of the adiposity spectrum. While variations in centrally acting factors, such as leptin, are well known to modulate adiposity, it has not been shown that variations in expression of a single gene acting in peripheral tissues can lead to both lipodystrophy and obesity. We previously identified lipin deficiency as a cause of lipodystrophy in the mouse, due to impaired adipocyte differentiation. Here we demonstrate that lipin levels in muscle are a determinant of energy metabolism, with null expression causing increased energy expenditure and fat utilization, and enhanced expression causing reduced energy expenditure and fat utilization, leading to obesity. Furthermore, replacement of lipin exclusively in muscle of lipin-deficient mice is sufficient to normalize energy expenditure. Thus, variations in lipin levels alone are sufficient to induce extreme states of adiposity, and may represent a mechanism by which skeletal muscle modulates fat mass and energy balance.