Fatty Acid Fate In Determining Oxidation And Inflammation In Adipose Tissue

Adipose tissue (AT) is a critical regulator of energy balance through its ability to store or oxidize free fatty acids (FFAs). White adipose tissue (WAT) functions as an anabolic organ to sequester and release FAs, in contrast brown adipose tissue (BAT) is a catabolic organ that oxidizes FAs. However, a comprehensive understanding of the role that FFAs play in the function of WAT and BAT is needed. Here we demonstrate that intracellular FAs enhance the expression of inflammatory cytokines by β3-AR activation in adipocytes, in which the expression of PAI-1 is partly mediated by the de novo synthesis of ceramides/sphingolipids. We also explored the relationship between lipolysis and oxidative gene expression in AT. β3-AR stimulation increased the expression of oxidative genes (PCG1á, UCP1 and NOR-1) in WAT of mice, which was greatly potentiated by inhibition of hormone sensitive lipase (HSL). In 3T3-L1 adipocytes, limiting lipolysis potentiated the induction of oxidative genes; while in contrast, promoting the accumulation of intracellular FAs suppressed their induction by Β-AR stimulation. Interrogation of the Β-adrenergic signalling pathway indicates that intracellular FAs inhibit adenylyl cyclase activity and thereby reduce PKA-mediated transcriptional activity. Partially limiting lipolysis enhanced the induction of brown fat markers and mitochondrial electron transport chain activity in WAT, and facilitated fat loss in mice treated with a β3-AR agonist for five days. In contrast to the results observed in WAT, HSL activity was required for the induction of PGC1α, PPARα, PDK4 and UCP1 by β3-AR activation in BAT of mice. Similarly, lipolysis was required for the maximal induction of oxidative genes in cultured brown adipocytes (BAs), while increasing endogenous FAs elevated their expression. Pharmacological antagonism and siRNA knockdown indicate that PPARα and δ mediate the induction of oxidative genes by Β-AR agonism. Dynamic imaging studies demonstrate that lipids droplets are a source of ligands that transcriptionally activate PPARα and δ. Finally, lipolysis was required to maintain the expression of mitochondrial genes, and FA oxidation in BA. Overall, results indicate that in WAT excess FFAs are toxic, and function to balance production with efflux, while in BAT FFAs promote oxidation, and match FA oxidation with supply. These finding suggest that limiting intracellular FAs is WAT, and activation of PPARα/δ would be of benefit in preventing the toxic effects of FAs, which could have implications for treating excess adiposity and diabetes

The prevalence and risk of metabolic syndrome and its components among people with posttraumatic stress disorder: A systematic review and meta-analysis

Objective: People with posttraumatic stress disorder (PTSD) have a higher mortality than the general population, mainly due to cardiovascular diseases (CVD). Metabolic syndrome (MetS) and its components are highly predictive of CVD. The aim of this meta-analysis was to describe pooled frequencies of MetS and its components in people with PTSD and to compare MetS prevalences in PTSD versus the general population. Method: Medline, PsycARTICLES, Embase and CINAHL were searched until 02/2015 for cross-sectional and baseline data of longitudinal studies in adults with PTSD. Two independent reviewers conducted the searches and extracted data. Random effects meta-analysis with a relative risk, subgroups and meta-regression analyses were employed. Results: Overall, 9 studies met the inclusion criteria including 9,254 individuals in midlife with PTSD and 6,852 general population controls. The pooled MetS prevalence was 38.7% (95%CI = 32.1%-45.6%; Q = 52.1, p < 0.001; N = 9; n = 9,673; age range = 44-61years). Abdominal obesity was observed in 49.3% (95%CI = 29.7%-69.0%), hyperglycaemia in 36.1% (95%CI = 18.8%-55.6%), hypertriglyceridemia in 45.9% (95%CI = 12.2%-81.9%), low high density-lipoprotein-cholesterol in 46.4% (95%CI = 26.4%-67.0%) and hypertension in 76.9% (95%CI = 67.9%-84.8). The MetS prevalence was consistently high across geographical regions, settings or populations (war veterans or not). Compared with matched general population controls, people with PTSD had an almost double increased risk for MetS (RR = 1.82; 95%CI = 1.72-1.92; p < 0.001). Most analyses were not statistically heterogeneous. Conclusions: MetS is highly prevalent in people with PTSD. Routine screening and multidisciplinary management of medical and behavioral conditions is needed. Future research should focus on how cardio-metabolic outcomes are moderated by clinical and treatment characteristics and genetic factors

Dynamic Changes in Lipid Droplet-Associated Proteins in the "Browning" of White Adipose Tissues

The morphological and functional differences between lipid droplets (LDs) in brown (BAT) and white (WAT) adipose tissues will largely be determined by their associated proteins. Analysing mRNA expression in mice fat depots we have found that most LD protein genes are expressed at higher levels in BAT, with the greatest differences observed for Cidea and Plin5. Prolonged cold exposure, which induces the appearance of brown-like adipocytes in mice WAT depots, was accompanied with the potentiation of the lipolytic machinery, with changes in ATGL, CGI-58 and G0S2 gene expression. However the major change detected in WAT was the enhancement of Cidea mRNA. Together with the increase in Cidec, it indicates that LD enlargement through LD-LD transference of fat is an important process during WAT browning. To study the dynamics of this phenotypic change, we have applied 4D confocal microscopy in differentiated 3T3-L1 cells under sustained β-adrenergic stimulation. Under these conditions the cells experienced a LD remodelling cycle, with progressive reduction on the LD size by lipolysis, followed by the formation of new LDs, which were subjected to an enlargement process, likely to be CIDE-triggered, until the cell returned to the basal state. This transformation would be triggered by the activation of a thermogenic futile cycle of lipolysis/lipogenesis and could facilitate the molecular mechanism for the unilocular to multilocular transformation during WAT browning. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease