Abstract
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.
Highlights
Excessive caloric intake and/or insufficient nutrients utilization result in increased fat accumulation in adipose tissue, adipocytes hypertrophy and hyperplasia and are often associated with induction of low grade inflammation of adipose tissue
In this study we showed that PLD1 and PLD2 suppress food intake
We showed that PLD2 and, to a lesser extent, PLD1 are highly expressed in hypothalamus, a major center of coordination of satiety and hunger inputs
Summary
Excessive caloric intake and/or insufficient nutrients utilization result in increased fat accumulation in adipose tissue, adipocytes hypertrophy and hyperplasia and are often associated with induction of low grade inflammation of adipose tissue. This leads to increased levels of lipids and inflammatory mediators and promotes peripheral insulin resistance which leads to T2D [1]. Caloric intake and energy consumption are tightly regulated by hormones and nervous system. Nutrients and afferent neurons are coordinated in the hypothalamus to control energy balance.
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