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The mammalian focal adhesion proteins Pinch1/2 activate integrins and promote cell-extracellular matrix adhesion and migration; however, their roles in adipose tissue and metabolism are unclear. Here we find that high-fat diet (HFD) feeding dramatically increases expression of Pinch1/2 proteins in white adipose tissue (WAT) in mice. Furthermore, expression of Pinch1 is largely upregulated in WAT in leptin-deficient ob/ob type 2 diabetic mice and obese humans. While mice with loss of Pinch1 in adipocytes or global Pinch2 do not display any notable phenotypes, deleting Pinch1 in adipocytes and Pinch2 globally significantly decreases body weight and WAT mass, but not brown adipose tissue mass, in HFD-fed, but not normal chow diet-fed, mice. Pinch loss ameliorates HFD-induced glucose intolerance and fatty liver. After HFD challenge, Pinch loss slightly but significantly accelerates energy expenditure. While Pinch loss decreases adipocyte size and alters adipocyte size distribution, it greatly accelerates cell apoptosis primarily in epididymal WAT and to a lesser extent in subcutaneous WAT. In vitro studies demonstrate that Pinch loss accelerates adipocyte apoptosis by activating the Bim/Caspase-8 pathway. In vivo, genetic ablation of Caspase-8 expression in adipocytes essentially abolishes the ameliorating effects of Pinch deficiency on obesity, glucose intolerance, and fatty liver in mice. Thus, we demonstrate a previously unknown function of Pinch in control of adipose mass, glucose, and fat metabolism via modulation of adipocyte apoptosis. We may define a novel target for the prevention and treatment of metabolic diseases, such as obesity and diabetes. [ABSTRACT FROM AUTHOR]

Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4-/- bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4-/- BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity. [ABSTRACT FROM AUTHOR]