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Obesity is strongly associated with metabolic syndrome, a combination of risk factors that predispose to the development of the cardiometabolic diseases: atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Prevention of metabolic syndrome requires novel interventions to address this health challenge. The objective of this study was the identification of candidate molecules for the prevention and treatment of insulin resistance and atherosclerosis, conditions that underlie type 2 diabetes mellitus and cardiovascular disease, respectively. We used an unbiased bioinformatics approach to identify molecules that are upregulated in both conditions by combining murine and human data from a microarray experiment and meta-analyses. We obtained a pool of eight genes that were upregulated in all the databases analysed. This included well known and novel molecules involved in the pathophysiology of type 2 diabetes mellitus and cardiovascular disease. Notably, matrix metalloproteinase 12 (MMP12) was highly ranked in all analyses and was therefore chosen for further investigation. Analyses of visceral and subcutaneous white adipose tissue from obese compared to lean mice and humans convincingly confirmed the up-regulation of MMP12 in obesity at mRNA, protein and activity levels. In conclusion, using this unbiased approach an interesting pool of candidate molecules was identified, all of which have potential as targets in the treatment and prevention of cardiometabolic diseases.

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes., Obesity prevalence seems to have plateaued at ~40% (refs. 1,2), suggesting that environmental penetrance (such as a hypercaloric diet or a sedentary lifestyle) is limited to a subpopulation of individuals [...]

Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1a and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications., Obesity is closely associated with many disorders, including atherosclerosis and type 2 diabetes (1), (2). Although excess caloric intake and decreased energy expenditure promote overall weight gain, visceral adiposity is [...]

Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-[kappa]B (NF-[kappa]B) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-[kappa]B and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-[kappa]B (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy- induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease., Osteoporosis is a major health problem particularly affecting the aging population. In industrialized societies, it is an endemic disease characterized by an imbalance in skeletal turnover (1). This leads to [...]

Background: This study assessed the predictive performance of inflammatory, hepatic, coagulation, and cardiac biomarkers in patients with prediabetes and diabetes mellitus hospitalized for COVID-19 in Austria. Methods: This was an analysis of a multicenter cohort study of 747 patients with diabetes mellitus or prediabetes hospitalized for COVID-19 in 11 hospitals in Austria. The primary outcome of this study was in-hospital mortality. The predictor variables included demographic characteristics, clinical parameters, comorbidities, use of medication, disease severity, and laboratory measurements of biomarkers. The association between biomarkers and in-hospital mortality was assessed using simple and multiple logistic regression analyses. The predictive performance of biomarkers was assessed using discrimination and calibration. Results: In our analysis, 70.8% had type 2 diabetes mellitus, 5.8% had type 1 diabetes mellitus, 14.9% had prediabetes, and 8.6% had other types of diabetes mellitus. The mean age was 70.3 ± 13.3 years, and 69.3% of patients were men. A total of 19.0% of patients died in the hospital. In multiple logistic regression analysis, LDH, CRP, IL-6, PCT, AST-ALT ratio, NT-proBNP, and Troponin T were significantly associated with in-hospital mortality. The discrimination of NT-proBNP was 74%, and that of Troponin T was 81%. The calibration of NT-proBNP was adequate (p = 0.302), while it was inadequate for Troponin T (p = 0.010). Conclusion: Troponin T showed excellent predictive performance, while NT-proBNP showed good predictive performance for assessing in-hospital mortality in patients with diabetes mellitus hospitalized with COVID-19. Therefore, these cardiac biomarkers may be used for prognostication of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Author(s): Nicholas M Morton; Jasmina Beltram; Roderick N Carter; Zoi Michailidou; Gregor Gorjanc; Clare McFadden; Martin E Barrios-Llerena; Sergio Rodriguez-Cuenca; Matthew T G Gibbins; Rhona E Aird; José Maria Moreno-Navarrete; [...]