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Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol’s leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol’s action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol’s metabolic actions. IL1R1 is a gatekeeper for celastrol’s metabolic actions.

Elevated endoplasmic reticulum (ER) stress is tightly associated with the development of obesity and insulin resistance. Previous reports showed that haploinsufficiency of X-box binding protein 1 (XBP1), one of the master regulators of ER protein folding function, results in obesity and type 2 diabetes. In our previous work, we showed that bromodomain-containing protein 7 (BRD7) regulates the nuclear translocation of XBP1 through its interaction with the regulatory subunits of phosphatidylinositol 3 kinase (PI3K), p85s. We reported that the expression levels of BRD7 are significantly reduced in the liver of obese mice and acute upregulation of hepatic BRD7 in obese and type 2 diabetic mice improves glucose homeostasis. In our current unpublished work, we show that nuclear translocation of BRD7 is independent of PI3K activity and p110, the catalytic subunit of PI3K, is not involved in the degradation of BRD7. We show that both whole-body reduction and liver-specific deletion of BRD7 lead to increased weight gain. We also show that sustained restoration of BRD7 in the liver starting at an early age protects mice from developing obesity, glucose intolerance, and insulin resistance even when challenged with a high-fat diet. Disclosure J.M. Lee: None. Y. Kim: None. M.A. Salazar Hernandez: None. S. Park: None. Funding American Diabetes Association (1-17-IBS-104 to S.P.); National Institutes of Health

Obesity is a debilitating disease that has become a global epidemic. Although progress is being made, the underlying molecular mechanism by which obesity develops still remains elusive. Recently, we reported that the expression levels of bromodomain-containing protein 7 (BRD7) are significantly reduced in the liver of obese mice. However, it is not clear whether decreased levels of hepatic BRD7 are directly associated with the development of obesity and disturbance in glucose homeostasis. Here, using heterozygous BRD7 knockout and liver-specific BRD7 knockout mouse models, we report that reduced BRD7 levels lead to increased weight gain with little effect on glucose metabolism. On the other hand, upregulating BRD7 in the liver starting at an early age protects mice from gaining excessive weight and developing glucose intolerance and insulin resistance when challenged with a high-fat diet.

Endoplasmic reticulum (ER) stress has been shown to contribute to various metabolic diseases, including non-alcoholic fatty liver disease and type 2 diabetes. Reduction of ER stress by treatment with chemical chaperones or overexpression of ER chaperone proteins alleviates hepatic steatosis. Nonetheless, X-box binding protein 1s (XBP1s), a key transcription factor that reduces ER stress, has been proposed as a lipogenic transcription factor. In this report, we document that XBP1s leads to suppression of lipogenic gene expression and reduction of hepatic triglyceride and diacylglycerol content in livers of diet-induced obese and genetically obese and insulin-resistant ob/ob mice. Furthermore, we also show that PKCϵ activity, which correlates with fatty liver and which causes insulin resistance, was significantly reduced in diet-induced obese mice. Finally, we have shown that XBP1s reduces the hepatic fatty acid synthesis rate and enhances macrolipophagy, an initiating step in lipolysis. Our results reveal that XBP1s reduces hepatic lipogenic gene expression and improves hepatosteatosis in mouse models of obesity and insulin resistance, which leads us to conclude that XBP1s has anti-lipogenic properties in the liver.

Elevated endoplasmic reticulum (ER) stress plays crucial roles in the development of insulin resistance, type 2 diabetes, and obesity. X-Box binding protein 1 (XBP1) is one of the master regulators of ER folding function and is involved in the regulation of ER stress. Haploinsufficiency of XBP1 leads to the development of obesity, insulin resistance, and type 2 diabetes even in mice on a background that is resistant to the development of obesity. To date, our understanding of the regulation of XBP1 in metabolic processes is still limited. In our previous work, we demonstrated that bromodomain containing protein 7 (BRD7) regulates glucose homeostasis by increasing the nuclear translocation of XBP1s through its interaction with the regulatory subunits of phosphatidyl inositol 3-kinase (PI3K), p85s. We also showed that BRD7 protein levels are significantly reduced in the liver of genetically obese ob/ob and high fat diet (HFD)-induced obese mouse models, and over-expression of BRD7 in the liver of ob/ob and HFD fed mice ameliorates hyperglycemia and glucose intolerance through increasing the activity of XBP1s. In our current unpublished work, we show that BRD7 heterozygous knockout mice are prone to developing obesity when they are challenged with a HFD. They display increased hepatic triglyceride levels with moderately severe steatosis. In addition, we generated a liver-specific BRD7 knockout mouse model (LBKO) to examine the effect of BRD7 specifically in the liver. LBKO mice fed on a HFD exhibit increased body weights compared to their wild type control mice. Downregulation of BRD7 in the liver led to lack of nuclear XBP1s in the liver in both the knockout mouse model and adenovirus-mediated knockdown system. Our results provide the first evidence that BRD7, which was originally reported as a tumor suppressor, is involved in the development of obesity as well as in the regulation of unfolded protein response (UPR) and glucose metabolism. Disclosure S. Park: None. Y. Han: None. M.A. Salazar Hernandez: None.

Objective Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism. Methods We investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. Results We show that PGC-1α interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction. Conclusions Our findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s., Highlights • XBP1s suppresses FoxO1 activity and hepatic gluconeogenesis. • PGC-1α physically interacts with XBP1s and functions as a co-suppressor of XBP1s in the liver. • The suppression of XBP1s activity by PGC-1α leads to impaired glucose homeostasis in obese mice. • Hepatic PGC-1α promotes gluconeogenesis as a co-activator and also as a co-suppressor.

The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.

Bromodomain-containing protein 7 (BRD7) is a member of bromodomain-containing protein family and its function has been implicated in several diseases. We have previously shown that BRD7 plays a role in metabolic processes. However, the effect of BRD7 deficiency in glucose metabolism and its role in in vivo have not been fully revealed. Here, we report the essential role of BRD7 during embryo development. Mice homozygous for BRD7 led to embryonic lethality at mid-gestation. Homozygous BRD7 knockout (KO) mice showed retardation in development, and eventually all BRD7 KO embryos died in utero prior to E16.5. Partial knockdown of Brd7 gene displayed mild changes in glucose metabolism.

It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKβ) is a crucial kinase that responds to inflammatory stimuli such as Tumor Necrosis Factor α (TNFα), by initiating a variety of intracellular signaling cascades, and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKβ-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKβ phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKβ activity in the liver of obese mice, and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKβ-mediated hepatic inflammation in glucose homeostasis.