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In the context of obesity and its related maladies, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis. An obese, hypertrophic adipocyte is challenged by many insults, including surplus energy, inflammation, insulin resistance, and considerable stress to various organelles. The endoplasmic reticulum (ER) is one such vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance. Under normal conditions, the ER must function in the unique and trying environment of the adipocyte, adapting to meet the demands of increased protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell. When nutrients are in pathological excess, the ER is overwhelmed and the unfolded protein response (UPR) is activated. Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress. This review will focus on the function of the ER under normal conditions in the adipocyte and the pathological effects of a stressed ER contributing to adipocyte dysfunction and a thwarted metabolic homeostasis. In the context of obesity and its related maladies, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis. An obese, hypertrophic adipocyte is challenged by many insults, including surplus energy, inflammation, insulin resistance, and considerable stress to various organelles. The endoplasmic reticulum (ER) is one such vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance. Under normal conditions, the ER must function in the unique and trying environment of the adipocyte, adapting to meet the demands of increased protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell. When nutrients are in pathological excess, the ER is overwhelmed and the unfolded protein response (UPR) is activated. Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress. This review will focus on the function of the ER under normal conditions in the adipocyte and the pathological effects of a stressed ER contributing to adipocyte dysfunction and a thwarted metabolic homeostasis. apoptosis signal-regulating kinase 1 activating transcription factor-6 C/EBP homologous protein ER degradation-enhancing α-mannosidase-like protein eukaryotic translational initiation factor 2α endoplasmic reticulum endoplasmic reticulum-resident DNAj homolog 4 ER redox control for endoplasmic reticulum oxidoreductin growth arrest and DNA damage-inducible protein inhibitor of NKκB IKB kinase nuclear factor κB interleukin-6 inositol-requiring enzyme-1 insulin receptor substrate 1 c-jun N-terminal kinase mammalian target of rapamycin nuclear factor κB oxygen-regulated protein phenyl butyric acid protein disulfide isomerase PKR-like eukaryotic initiation factor 2α kinase peroxisome proliferator-activated receptor γ reactive oxygen species sterol-regulatory element binding protein tumor necrosis factor-α triglyceride tumor necrosis factor receptor-associated factor 2 Tribbles 3/SKIP 3 taurine-conjugated ursodeoxycholic acid unfolded protein response X-box protein 1 The adipocyte and the adipose tissue it inhabits have begun to fascinate researchers as a result of rapidly accumulating new knowledge of their function and contribution to whole body metabolic homeostasis. Adipose tissue is highly specialized to store lipid and/or release energy from lipid stores in response to a variety of signals. Adipose tissue also functions as an endocrine organ, secreting specific hormones or adipokines, which act as potent messengers to distant organs such as muscle, liver, and brain, with the purpose of maintaining the body's energy balance and metabolic health. Recent interest in the study of adipocytes has burgeoned as a result of the increasing incidence of obesity worldwide. Approximately 1.1 billion adults are overweight and 400 million adults are obese (body mass index ⩾ 30) (1.The World Health ReportReducing Risks, Promoting Healthy Life: 2002. Geneva, Switzerland: World Health Organization2002Google Scholar). All parts of the earth, developed and now developing countries as well, face an alarming obesity epidemic and the emergence of a cluster of associated pathologies (2.Hossain P. Kawar B. Nahas M.El Obesity and diabetes in the developing world—a growing challenge.N. Engl. J. Med. 2007; 356: 213-215Crossref PubMed Scopus (1623) Google Scholar). Because of increased urbanization, adaptation of the Western diet, and sedentary lifestyle, obesity rates have tripled in the past two decades in areas such as India, China, and Southeast Asia. As a consequence, the prevalence of diabetes is also predicted to increase 150% or more by the year 2030 in these countries (2.Hossain P. Kawar B. Nahas M.El Obesity and diabetes in the developing world—a growing challenge.N. Engl. J. Med. 2007; 356: 213-215Crossref PubMed Scopus (1623) Google Scholar). Therefore, it is imperative to take action on multiple levels to prevent this global epidemic and to encourage the involvement of individuals and communities as well as medical, pharmaceutical, and food industries. Understanding the mechanisms underlying obesity and its associated disease cluster is also of great significance, as the need for new and more effective therapeutic strategies is more urgent than ever. The massive expansion of adipose tissue that occurs in obesity is associated with numerous pathologies, including insulin resistance, type 2 diabetes, cardiovascular disease, and cancer. Increased adiposity, and perhaps especially visceral adiposity, is well correlated with an increased risk of insulin resistance and the development of type 2 diabetes (3.Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (6390) Google Scholar). It is thought that this excessive or disproportionate gain of adipose tissue may be causal to its dysfunction at many levels. that has as a central of this dysfunction is (3.Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (6390) Google Scholar). as c-jun N-terminal kinase and nuclear factor κB are in obese adipose to increased of such as tumor necrosis factor-α interleukin-6 and of these have been to be to insulin and of insulin in and G.S. and PubMed Scopus Google G.S. Adipose of tumor necrosis role in insulin PubMed Scopus Google G.S. from insulin resistance in PubMed Scopus Google J. Inflammation and insulin 2006; PubMed Scopus Google Scholar). adipose tissue is with as well as possible insults, such as oxidative and stress to result in organelle in and the endoplasmic reticulum It is that a adipose tissue must its lipid for organs to a for This also as may the normal function of contributing to for the and as well as it that adipose dysfunction may be at the of pathologies, and an of its will be to the development of effective and therapeutic metabolic in an adipose in for this of insulin or peroxisome proliferator-activated receptor γ in adipocytes in in whole body insulin the of adipose tissue on energy balance as well as and lipid of the insulin action in and PubMed Scopus Google Adipose tissue insulin receptor obesity and PubMed Scopus Google P. J. peroxisome proliferator-activated receptor insulin resistance in fat and in PubMed Scopus Google Scholar). 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Gregor et al. (Thu,) studied this question.