The roles of PHLPPs in the regulation of tissue metabolism in pathophysiological state. (A) PHLPP2 suppresses de novo lipogenesis in the liver via interfering with prolonged Akt activation. Aging or obesity reduces the level of PHLPP2, resulting in the sustenance of the Akt signaling and hepatic steatosis. (B) In the pancreas, both PHLPP1 and PHLPP2 regulate pancreatic beta cell survival and proliferation. Insulin resistance drives pancreatic beta cell failure partially by upregulation of both PHLPP1 and PHLPP2 in response to high glucose exposure, which favors progression toward type 2 diabetes. (C) In adipose tissue, PHLPP1 or PHLPP2 controls insulin action and lipolysis. Obesity promotes PHLPP2 levels, which dephosphorylates HSL and causes glucose and lipid dysregulation. (D) In skeletal muscle, PHLPP1 plays crucial role in regulating insulin action. High circulating nutrient or ER stress potentiates increased PHLPP1 expression, contributing to insulin resistance.