Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice.
Akinrotimi Oludemilade,Riessen Ryan,VanDuyne Philip,Park Jung Eun,Lee Yoon Kwang,Wong Lee-Jun,Zavacki Ann M,Schoonjans Kristina,Anakk Sayeepriyadarshini
Hepatology (Baltimore, Md.)
Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr Shp double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator-activated receptor gamma 2 and lipid-droplet protein fat-specific protein 27 beta. CONCLUSION:These data suggest that Fxr and Shp inactivation may be beneficial to combat diet-induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854-1865).
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.
Watanabe Mitsuhiro,Houten Sander M,Mataki Chikage,Christoffolete Marcelo A,Kim Brian W,Sato Hiroyuki,Messaddeq Nadia,Harney John W,Ezaki Osamu,Kodama Tatsuhiko,Schoonjans Kristina,Bianco Antonio C,Auwerx Johan
While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.
Tournadre Anne,Vial Gaelle,Capel Frédéric,Soubrier Martin,Boirie Yves
Joint bone spine
Sarcopenia is defined as a combination of low muscle mass with low muscle function. The term was first used to designate the loss of muscle mass and performance associated with aging. Now, recognized causes of sarcopenia also include chronic disease, a physically inactive lifestyle, loss of mobility, and malnutrition. Sarcopenia should be differentiated from cachexia, which is characterized not only by low muscle mass but also by weight loss and anorexia. Sarcopenia results from complex and interdependent pathophysiological mechanisms that include aging, physical inactivity, neuromuscular compromise, resistance to postprandial anabolism, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, mitochondrial dysfunction, and inflammation. The prevalence of sarcopenia ranges from 3% to 24% depending on the diagnostic criteria used and increases with age. Among patients with rheumatoid arthritis 20% to 30% have sarcopenia, which correlates with disease severity. Sarcopenia exacts a heavy toll of functional impairment, metabolic disorders, morbidity, mortality, and healthcare costs. Thus, the consequences of sarcopenia include disability, quality of life impairments, falls, osteoporosis, dyslipidemia, an increased cardiovascular risk, metabolic syndrome, and immunosuppression. The adverse effects of sarcopenia are particularly great in patients with a high fat mass, a condition known as sarcopenic obesity. The diagnosis of sarcopenia rests on muscle mass measurements and on functional tests that evaluate either muscle strength or physical performance (walking, balance). No specific biomarkers have been identified to date. The management of sarcopenia requires a multimodal approach combining a sufficient intake of high-quality protein and fatty acids, physical exercise, and antiinflammatory medications. Selective androgen receptor modulators and anti-myostatin antibodies are being evaluated as potential stimulators of muscle anabolism.
Mechanisms Underlying Metabolic Syndrome-Related Sarcopenia and Possible Therapeutic Measures.
Rubio-Ruiz María Esther,Guarner-Lans Verónica,Pérez-Torres Israel,Soto María Elena
International journal of molecular sciences
Although there are several reviews that report the interrelationship between sarcopenia and obesity and insulin resistance, the relation between sarcopenia and the other signs that compose the metabolic syndrome (MetS) has not been extensively revised. Here, we review the mechanisms underlying MetS-related sarcopenia and discuss the possible therapeutic measures proposed. A vicious cycle between the loss of muscle and the accumulation of intramuscular fat might be associated with MetS via a complex interplay of factors including nutritional intake, physical activity, body fat, oxidative stress, proinflammatory cytokines, insulin resistance, hormonal changes, and mitochondrial dysfunction. The enormous differences in lipid storage capacities between the two genders and elevated amounts of endogenous fat having lipotoxic effects that lead to the loss of muscle mass are discussed. The important repercussions of MetS-related sarcopenia on other illnesses that lead to increased disability, morbidity, and mortality are also addressed. Additional research is needed to better understand the pathophysiology of MetS-related sarcopenia and its consequences. Although there is currently no consensus on the treatment, lifestyle changes including diet and power exercise seem to be the best options.