Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure. IntroductionThe chronic consumption of meals rich in fat and carbohydrates is a major causative factor of obesity and diabetes. The prevailing view on the mechanism by which these dietary factors contribute to obesity and diabetes is that when energy intake surpasses expenditure, the excess calories are deposited as fat in adipose tissues and its subsequent mobilization to nonadipose tissues causes insulin resistance that ultimately leads to type 2 diabetes (1-3). High fat and carbohydrate intake also leads to plasma lipid abnormalities, including high plasma levels of nonesterified fatty acids (NEFAs) and triglyceride-rich lipoproteins (TGRL) as well as reduced plasma levels of HDL (2, 3). Numerous past studies have shown that elevated plasma NEFA levels directly induce insulin resistance and thus play a causative role in the pathogenesis of obesity-related diabetes (1,4,5). However, only sporadic attention has been paid to the role of TGRL in obesity and diabetes. The TGRL are generally thought of primarily as triglyceride carriers in the circulation, delivering substrates to tissues where lipoprotein lipase-catalyzed (LpL-catalyzed) hydrolysis liberates NEFAs prior to their uptake by cells through CD36 and other pathways (6). It is important to note that TGRL as well as lipase-hydrolyzed TGRL remnants can also be internalized by cells directly via whole-particle uptake and provide triglyceride-derived fatty acids via mechanisms mediated by LDL receptor family member proteins (7). Results showing

During chronic caloric excess, adipose tissue expands primarily by enlargement of individual adipocytes, which become stressed with lipid overloading, thereby contributing to obesity-related disease. Although adipose tissue contains numerous preadipocytes, differentiation into functionally competent adipocytes is insufficient to accommodate the chronic caloric excess and prevent adipocyte overloading. We report for the first time that a chronic high-fat diet (HFD) impairs adipogenic differentiation, leading to accumulation of inefficiently differentiated adipocytes with blunted expression of adipogenic differentiation-specific genes. Preadipocytes from these mice likewise exhibit impaired adipogenic differentiation, and this phenotype persists during in vitro cell culture. HFD-induced impaired adipogenic differentiation is associated with elevated expression of histone deacetylase 9 (HDAC9), an endogenous negative regulator of adipogenic differentiation. Genetic ablation of HDAC9 improves adipogenic differentiation and systemic metabolic state during an HFD, resulting in diminished weight gain, improved glucose tolerance and insulin sensitivity, and reduced hepatosteatosis. Moreover, compared with wild-type mice, HDAC9 knockout mice exhibit upregulated expression of beige adipocyte marker genes, particularly during an HFD, in association with increased energy expenditure and adaptive thermogenesis. These results suggest that targeting HDAC9 may be an effective strategy for combating obesity-related metabolic disease.

Objective Perivascular adipose tissue (PVAT) expands during obesity, is highly inflamed, and correlates with coronary plaque burden and increased cardiovascular risk. We tested the hypothesis that PVAT contributes to the vascular response to wire injury and investigated the underlying mechanisms. Approach and Results We transplanted thoracic aortic PVAT from donor mice fed a high-fat diet (HFD) to the carotid arteries of recipient HFD-fed LDLR−/− mice. Two weeks after transplantation, wire injury was performed, and animals were sacrificed two weeks later. Immunohistochemistry was performed to quantify adventitial macrophage infiltration and neovascularization, and neointimal lesion composition and size. Transplanted PVAT accelerated neointimal hyperplasia, adventitial macrophage infiltration and adventitial angiogenesis. The majority of neointimal cells in PVAT-transplanted animals expressed α-smooth muscle actin, consistent with smooth muscle phenotype. Deletion of MCP-1 in PVAT substantially attenuated the effects of fat transplantation on neointimal hyperplasia and adventitial angiogenesis, but not adventitial macrophage infiltration. Conditioned medium from perivascular adipocytes induced potent monocyte chemotaxis in vitro and angiogenic responses in cultured endothelial cells. Conclusions These findings indicate that PVAT contributes to the vascular response to wire injury, in part through MCP-1-dependent mechanisms.

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