Obesity is a major risk factor predisposing to the development of peripheral
insulin resistance and
type 2 diabetes (T2D). Elevated food intake and/or decreased energy expenditure promotes
body weight gain and acquisition of adipose tissue. Number of studies implicated
phospholipase D (
PLD)
enzymes and their product,
phosphatidic acid (PA), in regulation of signaling cascades controlling energy intake, energy dissipation and metabolic homeostasis. However, the impact of
PLD enzymes on regulation of metabolism has not been directly determined so far. In this study we utilized mice deficient for two major
PLD isoforms, PLD1 and PLD2, to assess the impact of these
enzymes on regulation of metabolic homeostasis. We showed that mice lacking PLD1 or PLD2 consume more food than corresponding control animals. Moreover, mice deficient for PLD2, but not PLD1, present reduced energy expenditure. In addition, deletion of either of the
PLD enzymes resulted in development of elevated
body weight and increased adipose tissue content in aged animals. Consistent with the fact that elevated content of adipose tissue predisposes to the development of
hyperlipidemia and
insulin resistance, characteristic for the pre-diabetic state, we observed that Pld1-/- and Pld2-/- mice present elevated
free fatty acids (FFA) levels and are
insulin as well as
glucose intolerant. In conclusion, our data suggest that deficiency of PLD1 or PLD2 activity promotes development of
overweight and diabetes.