SUMMARY Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), a universal quality-control system in the cell; but its physiological role remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Further analyses reveal that Sel1L is indispensable for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and form protein aggregates, which are degraded primarily by autophagy. The Sel1L-mediated control of LPL secretion is also seen in other LPL-expressing cell types including cardiac myocytes and macrophages. Thus, our study reports a role of Sel1L in LPL secretion and systemic lipid metabolism.

dGlucose-dependent insulinotropic polypeptide (GIP), an incretin hormone secreted from gastrointestinal K cells in response to food intake, has an important role in the control of whole-body metabolism. GIP signals through activation of the GIP receptor (GIPR), a G-protein-coupled receptor (GPCR). Dysregulation of this pathway has been implicated in the development of metabolic disease. Here we demonstrate that GIPR is constitutively trafficked between the plasma membrane and intracellular compartments of both GIP-stimulated and unstimulated adipocytes. GIP induces a downregulation of plasma membrane GIPR by slowing GIPR recycling without affecting internalization kinetics. This transient reduction in the expression of GIPR in the plasma membrane correlates with desensitization to the effects of GIP. A naturally occurring variant of GIPR (E354Q) associated with an increased incidence of insulin resistance, type 2 diabetes, and cardiovascular disease in humans responds to GIP stimulation with an exaggerated downregulation from the plasma membrane and a delayed recovery of GIP sensitivity following cessation of GIP stimulation. This perturbation in the desensitization-resensitization cycle of the GIPR variant, revealed in studies of cultured adipocytes, may contribute to the link of the E354Q variant to metabolic disease. G lucose-dependent insulinotropic polypeptide (GIP) is secreted by K cells of the gastrointestinal tract in response to food (1, 2). GIP together with the other incretin hormone, glucagon-like peptide 1, have prominent roles in the control of wholebody energy metabolism. A primary function of these hormones is to stimulate glucose-dependent insulin release from pancreatic beta cells (3-5). In addition to its effect on the pancreas, GIP functions to regulate several aspects of adipocyte metabolism, including increasing the sensitivity of adipocytes to insulin, thereby setting the tone for an optimal insulin response (e.g., see references 6-13). GIP signals through the GIP receptor (GIPR), a Gprotein-coupled receptor (GPCR) coupled to the stimulatory G alpha subunit and elevated cyclic AMP (cAMP) levels (4,14,15).In individuals with type 2 diabetes mellitus (T2DM), GIP-mediated insulinotropic effects are attenuated despite normal to elevated levels of blood . This GIP resistance potentially contributes to the pathophysiology of T2DM. The importance of GIP function in metabolic homeostasis is highlighted by the discovery in genome-wide association studies of a number of single nucleotide polymorphisms in the GIPR gene linked to an increased risk of metabolic diseases, including insulin resistance, T2DM, and cardiovascular diseases (19-21). One of these variants results in the substitution of glutamine for glutamic acid at position 354 (E354Q) of GIPR, which has been shown in various studies to be associated with insulin resistance (22), cardiovascular disease (21), and defects in beta-cell function (23).Despite extensive characterization of GIP's effects on metabolism, little is known about the beha...

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