Aims/hypothesis Obesity is a global epidemic resulting from increased energy intake, leading to increased circulating free fatty acids, altering energy homeostasis and resulting in an imbalance in fat storage and breakdown. G0/G1 switch gene 2 (G0S2) has been recently characterized in vitro as an inhibitor of Adipose triglyceride lipase (ATGL), the rate-limiting step in fat catabolism. In the current study we aim to functionally characterize G0S2 within the physiological context of a mouse model. Methods We generated a mouse model in which G0S2 was deleted. G0S2 knockout mice were studied over a period of 22 weeks. Metabolic parameters were measured including body weight and body composition, food intake, glucose and insulin tolerance tests, energy metabolism and thermogenesis. Results We report that G0S2 inhibits ATGL and regulates lipolysis and energy metabolism in vivo. G0S2-knockout mice are lean, resistant to weight gain induced by high fat diet feeding and are glucose tolerant and insulin sensitive. White adipose tissues of G0S2-knockout mice have enhanced lipase activity and adipocytes showed enhanced stimulated lipolysis. Energy metabolism in the knockout mice is shifted toward enhanced lipid metabolism and increased thermogenesis. G0S2 knockout mice showed enhanced cold tolerance and increased expression of thermoregulatory and oxidation genes within white adipose tissue suggesting enhanced “browning” of the knockout-white adipose tissues. Conclusions/Interpretation Our data show that G0S2 is a physiological regulator of adiposity and energy metabolism and is a potential target in the treatment of obesity and insulin resistance.

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Both CCKR subtypes occupy RIN-14B cells and initiate SS secretion through constitutive secretion controlled at SS synthesis level. Somatostatin secretion via the CCK-1R occupation mobilizes its high-affinity sites.

With the exclusive presence of the pancreatic CCK-2 receptors on the pancreatic delta cells of six different species, this study was undertaken to determine the role of cholecystokinin and gastrin on growth of these somatostatin (SS) cells. For this study, the SS-RIN-14B cells were used in culture and their growth was evaluated by cell counting. Results. To our surprise, we established by Western blot that these RIN cells possess the two CCK receptor subtypes, CCK-1 and CCK-2. Occupation of the CCK-1 receptors by caerulein, a CCK analog, led to inhibition of cell proliferation, an effect prevented by a specific CCK-1 receptor antagonist. Occupation of the CCK-2 receptors by the gastrin agonist pentagastrin had no effect on cell growth. Proliferation was not affected by SS released from these cells but was inhibited by exogenous SS. Conclusions. Growth of the SS-RIN-14B cells can be negatively affected by occupation of their CCK-1 receptors and by exogenous somatostatin.

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