The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.

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.-Gregor, M. F., and G. S. Hotamisligil. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J. Lipid Res.

OBJECTIVE-Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss. RESEARCH DESIGN AND METHODS-Eleven obese menand women (BMI 51.3 Ϯ 3.0 kg/m 2 ) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers.RESULTS-Subjects lost 39 Ϯ 9% body wt at 1 year after GBP surgery (P Ͻ 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2␣ (eIF2␣) and stress kinase c-Jun NH 2 -terminal kinase 1 (JNK1) (all P values Ͻ0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2␣ before surgery, which was reduced in post-GBP sections.CONCLUSIONS-This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans. Diabetes 58:693-700, 2009

OBJECTIVEInsulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women.RESEARCH DESIGN AND METHODSTwenty obese subjects ([means ± SD] aged 48 ± 11 years, BMI 37 ± 4 kg/m2) were randomized to 4 weeks of treatment with TUDCA (1,750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signaling, and cellular markers of ER stress.RESULTSHepatic and muscle insulin sensitivity increased by ∼30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrateTyr and AktSer473 levels) (P < 0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo.CONCLUSIONSThese data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.

Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in integrating inflammatory and metabolic responses and thus plays a key role in systemic metabolic homeostasis.

Summary The adipocyte is central to organismal metabolism and exhibits significant functional and morphological plasticity during its formation and lifespan. Remarkable transformations of this organ occur during obesity and lactation, two metabolic processes where a better understanding of adipocyte function is essential. Considering the critical importance of the cellular organelle endoplasmic reticulum (ER) in adapting to fluctuations in synthetic processes, we explored the role of XBP1, a central regulator of ER adaptive responses, in adipocyte formation and function. Unexpectedly, deletion of adipocyte-XBP1 in vivo in mice (XBP1ΔAd) had no effect on adipocyte formation or systemic homeostatic metabolism on regular or high fat diet. However, during lactation XBP1ΔAd dams displayed increased adiposity, decreased milk production, and decreased litter growth compared to control dams. Moreover, we demonstrate that XBP1 is regulated during lactation, where it responds to prolactin to alter lipogenic gene expression. These results demonstrate a previously unrecognized role for adipocyte-XBP1 in regulation of lactational metabolism.

Background: Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. Methods: 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. Results: ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPαmediated STAMP2 expression. Conclusion: These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.

Background: Polycystic ovary syndrome (PCOS) affects 5%-15% of women of reproductive age and has a negative impact on their fertility. The primary outcome of this study is ovulation rate when standard (immediate release) metformin (MF) is added to clomiphene citrate (CC) in oligoovulatory and anovulatory women with PCOS. Methods: This is a randomized, double-blind, placebo-controlled trial. Twenty-seven women with PCOS (according to the Rotterdam consensus), desiring pregnancy and without another cause of subfertility were recruited from a public hospital outpatient gynecology clinic. Up to six cycles of CC (25-150 mg) plus either MF 500 mg tds (CC+MF) or placebo (CC+Pl) were offered. Student’s t-test, Chi-squared test, and Fisher’s exact test were used for analysis. Results: Thirteen women with up to six cycles each were included in the final analysis. The rate of ovulation and ovulation rate per cycle was similar between women in the CC+MF and CC+Pl groups RR 1.09 (95% CI 0.80-1.49) and RR 0.88 (95% CI 0.63-1.22), respectively as was chemical pregnancy rate RR 1.77 (95% CI 0.58-5.38). The live birth rate was higher in CC+MF RR 6.83 (95% CI 0.83-56.27) and miscarriage rate was lower RR 0.21 (95% CI 0.002-1.07). The number needed to treat for live birth was 10. Conclusion: Use of standard MF, 500 mg tds, when given with CC results in an increase in live birth rate, and a decrease in miscarriage rate.