Sungsoon Fang

Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

Depletion of fat-resident Treg cells prevents age-associated insulin resistance

Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.

Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance

The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)mRID1 in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRTmRID1 mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRTmRID1 mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRTmRID1 mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases.

Microbiology: Wealth management in the gut

People whose guts contain a low diversity of bacteria are found to have higher levels of body fat and inflammation than those with high gut-microbial richness. But dietary intervention can help. See Article p.541 & Letter p.585 Obesity is a risk factor for cardiovascular disease, diabetes, osteoporosis and other conditions including some cancers. Other influences must be at work to determine which, if any, metabolic diseases obese individuals will suffer, and two papers in this issue of Nature look at the role one of these factors, the richness of the gut microbiome. Le Chatelier et al. analysed the gut microbial gene composition in non-obese and obese individuals and found marked differences in gene and species richness. Individuals with low richness exhibited increased adiposity, insulin resistance, dyslipidaemia and inflammation. Obese individuals with low microbial richness tended to gain more body weight than those with high microbial richness. The authors also demonstrate that analysis of just a few bacterial marker species was sufficient to distinguish between high and low bacterial richness. Cotillard et al. monitored gut microbe profiles during diet-induced weight loss and weight stabilization interventions in obese or overweight individuals. They report that increased consumption of high-fibre foods, such as fruit and vegetables, leads to an increase in bacterial richness and improves some clinical symptoms associated with obesity. This finding supports previous work linking diet to the composition of gut microbe populations, and suggests that a permanent change might be achieved by appropriate diet.

Essential roles of bile acid receptors FXR and TGR5 as metabolic regulators

Alterations of bile acid (BA) metabolism in type II diabetes (T2D) have revealed a link between BAs and metabolic homeostasis. The BA receptors farnesoid X receptor (FXR) and G-protein coupled BA receptor 1 (TGR5) both have shown to regulate lipid, glucose, and energy metabolism, rendering them potential therapeutic targets for T2D therapy. Astonishingly, BA signaling is vital as it has known to be a positive factor for beneficial improvements in vertical sleeve gastrectomy surgery, in turn making these BA receptors beneficial tools in therapeutic targets for T2D. These metabolic regulators: FXR and TGR5 are essential modulators in the metabolic system, which affect the human machinery and will be the focus of this review.

Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis

Significance Retinoic acid (RA) is an important transcriptional regulator during both vertebrate and invertebrate body pattern formation. The Homeobox (Hox) gene family is activated by a gradient of RA formed along the length of the embryo at specific time points during fetal development. Generation of a genetically modified mouse harboring mutations in the SMRT repressor demonstrated that SMRT-dependent repression of retinoic acid receptor (RAR) is critical to establish and maintain the somitic Hox code and segmental identity during fetal development via epigenetic marking of target loci. Nuclear hormone receptors (NRs), such as retinoic acid receptors (RARs), play critical roles in vertebrate development and homeostasis by regulating target gene transcription. Their activity is controlled by ligand-dependent release of corepressors and subsequent recruitment of coactivators, but how these individual receptor modes contribute to development are unknown. Here, we show that mice carrying targeted knockin mutations in the corepressor Silencing Mediator of Retinoid and Thyroid hormone receptor (SMRT) that specifically disable SMRT function in NR signaling (SMRTmRID), display defects in cranial neural crest cell-derived structures and posterior homeotic transformations of axial vertebrae. SMRTmRID embryos show enhanced transcription of RAR targets including Hox loci, resulting in respecification of vertebral identities. Up-regulated histone acetylation and decreased H3K27 methylation are evident in the Hox loci whose somitic expression boundaries are rostrally shifted. Furthermore, enhanced recruitment of super elongation complex is evident in rapidly induced non-Pol II-paused targets in SMRTmRID embryonic stem cells. These results demonstrate that SMRT-dependent repression of RAR is critical to establish and maintain the somitic Hox code and segmental identity during fetal development via epigenetic marking of target loci.