The ability of the anti-diabetic drug metformin to inhibit anabolic processes including gluconeogenesis and lipogenesis is partly attributable to activation of the AMP-activated protein kinase (AMPK) pathway. The p160 steroid receptor coactivator 2 (SRC-2) is a key regulator of cellular metabolism and drives expression of the gluconeogenic enzyme glucose-6-phosphatase (G6Pc). Here, we uncovered a role for SRC-2 in the metabolic reprogramming imposed by metformin. In FaO cells, metformin dose-dependently reduced mRNA expression of SRC-2. Microarray analysis of metformin-treated cells revealed an overrepresentation of downregulated genes involved in biosynthesis of lipids and cholesterol. Several metformin-regulated genes including fatty acid synthase (FASN) were validated as transcriptional targets of SRC-2 with promoters characterized by sterol regulatory element (SRE) binding protein (SREBP) recognition sequences. Transactivation assays of the FASN promoter confirmed that SRC-2 is a coactivator of SREBP-1. By suppressing SRC-2 at the transcriptional level, metformin impeded recruitment of SRC-2 and RNA polymerase II to the G6Pc promoter and to SREs of mutual SRC-2/SREBP-1 target gene promoters. Hepatocellular fat accretion was reduced by metformin or knock-down of both SRC-2 and SREBP-1. Accordingly we propose that metformin inhibits glucose and lipid biosynthesis partly by downregulating SRC-2 gene expression.

Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer. We here aimed to identify novel transcriptional regulators of COL6A3 expression. Based on a transcriptome dataset of adipose tissue, we identified strong correlations for 56 genes with COL6A3 mRNA, including targets of TGF-β/SMAD signaling. Among the identified candidates, the homeobox transcription factor PRRX1 showed a particularly striking co-expression with COL6A3, validated across several different cohorts, including patients with extreme obesity, insulin sensitive and resistant obesity (subcutaneous and omental), after profound fat loss (subcutaneous), and lean controls (subcutaneous). In human and mouse adipose cells, PRRX1 knockdown reduced COL6A3 mRNA and PRRX1 overexpression transactivated a reporter construct with the endogenous human COL6A3 promoter. Stable PRRX1 overexpression in 3T3-L1 cells induced Col6a3 mRNA threefold specifically after adipogenic induction, whereas TGF-β1 treatment upregulated Col6a3 mRNA also in the preadipocyte state. Interestingly, pro-inflammatory stimulus (i.e., TNF-α treatment) decreased PRRX1-mediated Col6a3 transactivation and mRNA expression, supporting a role for this mechanism in the regulation of adipose tissue inflammation. In conclusion, we identified the homeobox factor PRRX1 as a novel transcriptional regulator associated with COL6A3 expression, providing new insight into the regulatory mechanisms of altered adipose tissue function in obesity and insulin resistance.

One might expect that a perception of obesity being a risk factor and disease, contributes to effective obesity prevention and management strategies. However, obesity rates continue to increase worldwide. The question arises whether obesity is truly perceived as a risk factor and a disease. This paper aims at describing perception of obesity as risk factor and disease among individuals seeking care, individuals not seeking care, the society, and different professionals having a role in the field of obesity. The paper is a reflection of the lecture on the topic that was given at the EASO's New Investigators United's Summer School 2016 in Portugal and the discussion with the new investigators and other senior speakers. Individual obese patients seeking help are very much aware of obesity being a risk factor and disease, but perceptions regarding obesity seem to be flawed among those who do not seek help for obesity. Also, misperceptions regarding obesity play a role at different levels, including society, different political levels, the fields of health care and social work, prevention organizations, and the food and marketing industry. The food and marketing industry has an enormous role in changing perceptions by the society and policy makers. Obesity rates will continue to increase as long as individuals, the society, and professionals at different levels have false interpretations of the severity of obesity. Severe action is needed against those who are playing a role in maintaining false perceptions of obesity as a risk factor and disease.

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor–associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5 ^−/− mice consumed a high-fat diet for 18 weeks. Traf5 ^−/− mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5 ^−/− mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5 ^−/− mice revealed an increase in cytotoxic T cells, CD11c ⁺ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNFα, MIP (macrophage inflammatory protein)-1α, MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5 -deficient adipocytes but not in Traf5 -deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.