Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity

The endocannabinoid system has been suspected to contribute to the association of visceral fat accumulation with metabolic diseases. We determined whether circulating endocannabinoids are related to visceral adipose tissue mass in lean, subcutaneous obese, and visceral obese subjects (10 men and 10 women in each group). We further measured expression of the cannabinoid type 1 (CB(1)) receptor and fatty acid amide hydrolase (FAAH) genes in paired samples of subcutaneous and visceral adipose tissue in all 60 subjects. Circulating 2-arachidonoyl glycerol (2-AG) was significantly correlated with body fat (r = 0.45, P = 0.03), visceral fat mass (r = 0.44, P = 0.003), and fasting plasma insulin concentrations (r = 0.41, P = 0.001) but negatively correlated to glucose infusion rate during clamp (r = 0.39, P = 0.009). In visceral adipose tissue, CB(1) mRNA expression was negatively correlated with visceral fat mass (r = 0.32, P = 0.01), fasting insulin (r = 0.48, P < 0.001), and circulating 2-AG (r = 0.5, P < 0.001), whereas FAAH gene expression was negatively correlated with visceral fat mass (r = 0.39, P = 0.01) and circulating 2-AG (r = 0.77, P < 0.001). Our findings suggest that abdominal fat accumulation is a critical correlate of the dysregulation of the peripheral endocannabinoid system in human obesity. Thus, the endocannabinoid system may represent a primary target for the treatment of abdominal obesity and associated metabolic changes

Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio

Objective:We hypothesized that genes within recently identified loci associated with waist-hip ratio (WHR) exhibit fat depot-specific mRNA expression, which correlates with obesity-related traits.Methods:Adipose tissue (AT) mRNA expression of 6 genes (TBX15/WARS2, STAB1, PIGC, ZNRF3 and GRB14) within these loci showing coincident cis-expression quantitative trait loci was measured in 222 paired samples of human visceral (vis) and subcutaneous (sc) AT. The relationship of mRNA expression levels with obesity-related quantitative traits was assessed by Pearson's correlation analyses. Multivariate linear relationships were assessed by generalized linear regression models.Results:Whereas only PIGC, ZNFR3 and STAB1 mRNA expression in sc AT correlated nominally with WHR (P<0.05, adjusted for age and sex), mRNA expression of all studied genes in at least one of the fat depots correlated significantly with vis and/or sc fat area (P ranging from 0.05 to 4.0 × 106, adjusted for age and sex). Consistently, the transcript levels of WARS, PIGC and GRB14 were nominally associated with body mass index (BMI) (P ranging from 0.02 to 9.2 × 105, adjusted for age and sex). Moreover, independent of sex, obesity and diabetes status, differential expression between vis and sc AT was observed for all tested genes (P<0.01). Finally, the rs10195252 T-allele was nominally associated with increased GRB14 sc mRNA expression (P=0.025 after adjusting for age, sex and BMI).Conclusions:Our data including the inter-depot variability of mRNA expression suggests that genes within the WHR-associated loci might be involved in the regulation of fat distribution. © 2014 Macmillan Publishers Limited

Dissociation between brown adipose tissue¹⁸F-FDG uptake and thermogenesis in uncoupling protein 1 deficient mice.

F-18-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis, which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain, however, whether BAT F-18-FDG uptake is a reliable surrogate measure of UCP1-mediated heat production. Methods: UCP1 knockout (KO) and wild-type (WT) mice housed at thermoneutrality were treated with the selective beta 3 adrenergic receptor agonist CL 316, 243 and under-went metabolic cage, infrared thermal imaging and F-18-FDG PET/MRI experiments. Primary brown adipocytes were additionally examined for their bioenergetics by extracellular flux analysis as well as their uptake of 2-deoxy-H-3-glucose. Results: In response to CL 316, 243 treatments, oxygen consumption, and BAT thermogenesis were diminished in UCP1 KO mice, but BAT F-18-FDG uptake was fully retained. Isolated UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-H-3-glucose uptake rates were largely unaffected. Conclusion: Adrenergic stimulation can increase BAT F-18-FDG uptake independently of UCP1 thermogenic function

Effects of Prunus cerasus L. seeds and juice on liver steatosis in an animal model of diet-induced obesity.

Visceral adipose tissue (VAT) has emerged as a major player in driving obesity-related inflammatory response [1]. In obesity, chronic infiltration of macrophages in adipose tissue mediates local and systemic inflammation [2]. In overweight individuals, a dangerous feedback loop may develop: increased VAT leads to chronic inflammation, which, in turn, leads to insulin resistance promoting VAT storage and enhances susceptibility to disease [3]. VAT mass is also a major determinant of endothelial dysfunction, liver steatosis, plasma adiponectin level, atherosclerosis and metabolic syndrome [4]. The tart cherries (Prunus Cerasus L.) juices were found to contain expected abundances of anthocyanins and flavonoids [5]. These components can modify lipid metabolism in vitro, reduce hyperlipidemia in vivo and possess high antioxidant activity [6]. Tart cherry seed contains unsaturated fatty acids, oleic acids, various bioactive structures such as polyphenols, flavonoids, vegetable acids, and pro- and anthocyanidins, which could have a useful therapeutic effect in the prevention of various vascular diseases [7]. The purpose of this study was to investigate the effects of tart cherries seeds and juice on adipogenesis and inflammation in VAT of rats fed with a high-fat diet. Diet-induced obesity (DIO) rats were used, because share many characteristics with human obesity [8]. For 17 weeks, rats were fed with a hypercaloric diet supplemented with tart cherries seeds powder (DS) and seeds powder plus tart cherries juice (DJS). DIO rats were compared to the control rats fed with a standard diet (CHOW). In VAT, the expression of PPARγ, SREBP-1c, p53, NF-κB, TNF-, CcL2, CD-68 were measured by qRT-PCR, western blot, and immunohistochemistry techniques. The DIO rats demonstrated significant increases in body weight compared to the CHOW rats. No difference in VAT weight was found in DS and DJS rats compared to age-matched DIO rats. However, tart cherries supplementation seems to modulate VAT depot by downregulating several adipocyte-specific transcription factors, including SREBP-1c and PPARγ, which play a critical role in the activation of adipogenesis. Moreover, the increased levels of inflammatory markers, induced by the diet in DIO rats, was modulated by tart cherries supplementation. These results suggest that tart cherries enriched-diet, although did not modify the accumulation of VAT, decreases inflammation and adipogenesis. Therefore, the addition of tart cherry to the diet and lifestyle interventions may modify adipose tissue cells metabolism, induce preferential mobilization of visceral fat and reduce the obesity-related multiple organ injuries