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The farnesoid X receptor (FXR) is a nuclear receptor whose activation leads to alterations in pathways involved in energy metabolism. For example, it serves as a bile acid receptor in tissues such as the liver, and as an energy metabolism regulator in liver, muscle and adipose tissue. However, the effects of FXR activation are not exclusive to the tissue where it is present, because receptor crosstalk affects tissues throughout the body. It has been demonstrated that FXR regulates the metabolism of not just bile acids, but also of fats and hydrocarbon metabolites. FXR is currently under study as a therapeutic target for the treatment of diseases of excess, such as diabetes. Here we review the effects of FXR activation in the response of an organism to excess energy. [ABSTRACT FROM AUTHOR]

Bile acids have been known to be potent anti-obesity agents both in vitro and in vivo. While the mechanism in vivo appears to hinge on thermogenic dissipation of excess nutrients, the fact that they are also effective in vitro and in animals with low non-shivering thermogenic capacity points to the fact that the mechanisms in play are yet to be fully demonstrated. 3T3-L1 adipocytes were infected with a CRISPR/Cas9-carrying lentivirus, which specifically targeted the bile acid receptor TGR5, and several metabolic assays were conducted. The absence of TGR5 was insufficient to eliminate CDCA's effects. In fact, mitochondrial respiration measured with a Seahorse flux analyzer and metabolic screening by NMR clearly demonstrate that CDCA can act through other means. Gene expression and protein content all point to elevated mitochondrial activity, increased oxidative capacity of both glucose and triglycerides, an effect already known but not totally removed by the absence of TGR5. Our data supports our previous findings that thermogenic dissipation is far from the only way by which bile acids reduce obesity. Further studies will confirm if the other known bile acid receptor, FXR, is also involved and/ or if other mechanisms of energy waste are also in play. [ABSTRACT FROM AUTHOR]

The key role of mitochondria in oxidative metabolism and redox homeostasis explains the link between mitochondrial dysfunction and the development of metabolic disorders. Mitochondria's highly dynamic nature, based on alterations in biogenesis, mitophagy, fusion and fission, allows adjusting sequential redox reactions of the electron transport chain (ETC) and dissipation of the membrane potential by ATP synthase, to different environmental cues. With reactive oxygen species being an inevitable by-product of oxidative phosphorylation (OXPHOS), alterations on mitochondrial oxidative rate with a consequent excessive load of reactive oxygen species have been traditionally associated with pathological conditions. However, reactive oxygen species have also been suggested as promoters of mitohormesis, a process in which low, non-cytotoxic concentrations of reactive oxygen species promote mitochondrial homeostasis. Therefore, signaling systems involved in the regulation of mitochondrial homeostasis are attractive candidates for drug development for metabolic diseases triggered by mitochondrial dysfunction. Reversible phosphorylation downstream the cyclic AMP (cAMP) signaling cascade and deacetylation mediated by sirtuins are recognized as major mitochondrial regulators. Image 1 • Mild increase in ROS generation triggers an adaptive mitochondrial response. • Induction of mitophagy by mild stress is required for mitochondrial homeostasis. • Phosphorylation and deacetylation of mitochondrial proteins are major regulatory mechanisms. • Mitochondrial homeostasis is modulated by the crosstalk between cAMP and SIRTs. [ABSTRACT FROM AUTHOR]

Autophagy is a pro-survival process that occurs under stressful “life-threatening” conditions. This process clears the cells of damaged organelles, long-lived proteins, and/or misfolded proteins. Under stressful conditions, activation of the autophagic process leads to cell death and acts as a protective mechanism against xenobiotic, which is the most widely accepted mechanism in the literature. Exposure to flame retardants and other pollutants is associated with several diseases, during which cell death and mitochondrial damage takes place. Although a body of research has aimed to understand the toxicity mechanism of flame retardants better, risk evaluation and the consequences of exposure to these toxicants have been poorly described. In this work, we have found that the BDE-153 congener (representant of flame retardants) induces autophagy after 24 and 48 h (0.1–25 μM). The autophagic process is associated with accumulation of lysosomes, and process triggering is evident from the levels of autophagy-related proteins such as p62 and LC3. Mitophagy (an autophagic process that specifically involves damaged mitochondria) may be involved, as judged from the decreased amount of mitochondrial DNA. Taken together, our results point out that induction of autophagy upon cell should contribute to better understanding of the consequences of human exposure to this class of environmental contaminants. [ABSTRACT FROM AUTHOR]