Obesity is a major risk factor for developing nonalcoholic fatty-liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty-liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity due to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiologic significance, hepatic ROCK1 was markedly up-regulated in humans with fatty-liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1-AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used anti-diabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1-AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.

Describing diet-related effects on the gut microbiome is essential for understanding its interactions with fat and/or sugar-rich diets to promote obesity-related metabolic diseases. Here, we sequenced the V3-V4 hypervariable region of the bacterial 16S rRNA gene to study the composition and dynamics of the gut microbiome of adult mice fed diets rich in fat and/or sugar, at 9 and 18 weeks of diet. Under high-fat, high-sugar diet, the abundances of Tuzzerella and Anaerovorax were transiently increased at 9 weeks, while Lactobacillus remained elevated at 9 and 18 weeks. The same diet decreased the abundances of Akkermansia, Paludicola, Eisenbergiella, and Butyricicoccus at 9 and 18 weeks, while Intestinimonas and UCG-009 of the Butyricicoccaceae family responded only at 18 weeks. The high-fat diet decreased the abundances of UBA1819 at 9 weeks, and Gastranaerophilales, Clostridia UCG-014, and ASF356 at 9 and 18 weeks. Those of Marvinbryantia, Harryflintia, Alistipes, Blautia, Lachnospiraceae A2, Eubacterium coprostanoligenes group, and Eubacterium brachy group were lowered only at 18 weeks. Interestingly, these genera were not sensitive to the high-sugar diet. The mouse gut microbiome was differentially affected by diets rich in fat or fat and sugar. The differences observed at 9 and 18 weeks indicate a progressive microbiome response.

Background: Cardiovascular diseases (CVDs) are a leading risk factor for mortality worldwide and the number of CVDs victims is predicted to rise through 2030. While several external parameters (genetic, behavioral, environmental and physiological) contribute to cardiovascular morbidity and mortality; intrinsic metabolic and functional determinants such as insulin resistance, hyperglycemia, inflammation, high blood pressure and dyslipidemia are considered to be dominant factors.Methods: Pubmed searches were performed using different keywords related with mitochondria and cardiovascular disease and risk. In vitro, animal and human results were extracted from the hits obtained.Results: High cardiac energy demand is sustained by mitochondrial ATP production, and abnormal mitochondrial function has been associated with several lifestyle- and aging-related pathologies in the developed world such as diabetes, non-alcoholic fatty liver disease (NAFLD) and kidney diseases, that in turn can lead to cardiac injury. In order to delay cardiac mitochondrial dysfunction in the context of cardiovascular risk, regular physical activity has been shown to improve mitochondrial parameters and myocardial tolerance to ischemia-reperfusion (IR). Furthermore, pharmacological interventions can prevent the risk of CVDs. Therapeutic agents that can target mitochondria, decreasing ROS production and improve its function have been intensively researched. One example is the mitochondria-targeted antioxidant MitoQ10, which already showed beneficial effects in hypertensive rat models. Carvedilol or antidiabetic drugs also showed protective effects by preventing cardiac mitochondrial oxidative damage.Conclusion: This review highlights the role of mitochondrial dysfunction in CVDs, also show-casing several approaches that act by improving mitochondrial function in the heart, contributing to decrease some of the risk factors associated with CVDs.

Background: In MASLD (formerly called NAFLD) mouse models, oversupply of dietary fat and sugar is more lipogenic than either nutrient alone. Fatty acids suppress de novo lipogenesis (DNL) from sugars, while DNL inhibits fatty acid oxidation. How such factors interact to impact hepatic triglyceride levels are incompletely understood. Methods: Using deuterated water, we measured DNL in mice fed 18-weeks with standard chow (SC), SC supplemented with 55/45-fructose/glucose in the drinking water at 30% (w/v) (HS), high-fat chow (HF), and HF with HS supplementation (HFHS). Liver glycogen levels and its sources were also measured. For HS and HFHS mice, pentose phosphate (PP) fluxes and fructose contributions to DNL and glycogen were measured using [U-¹³C]fructose. Results: The lipogenic diets caused significantly higher liver triglyceride levels compared to SC. DNL rates were suppressed in HF compared to SC and were partially restored in HFHS but supplied a minority of the additional triglyceride in HFHS compared to HF. Fructose contributed a significantly greater fraction of newly synthesized saturated fatty acids compared to oleic acid in both HS and HFHS. Glycogen levels were not different between diets, but significant differences in Direct and Indirect pathway contributions to glycogen synthesis were found. PP fluxes were similar in HS and HFHS mice and were insufficient to account for DNL reducing equivalents. Conclusions: Despite amplifying the lipogenic effects of fat, the fact that sugar-activated DNL per se barely contributes suggests that its role is likely more relevant in the inhibition of fatty acid oxidation. Fructose promotes lipogenesis of saturated over unsaturated fatty acids and contributes to maintenance of glycogen levels. PP fluxes associated with sugar conversion to fat account for a minor fraction of DNL reducing equivalents.

Dietary glucose and fructose are both efficiently assimilated by the liver but a comprehensive measurement of this process starting from their conversion to sugar phosphates, involvement of the pentose phosphate pathway (PPP), and conversion to glycogen and lipid storage products, remains incomplete. Mice were fed a chow diet supplemented with 35 g/100 mL drinking water of a 55/45 fructose/glucose mixture for 18 weeks. On the final night, the sugar mixture was enriched with either [U-¹³C]glucose or [U-¹³C]fructose, and deuterated water (²H₂O) was also administered. ¹³C-isotopomers representing newly synthesized hepatic glucose-6-phosphate (glucose-6-P), glycerol-3-phosphate, and lipogenic acetyl-CoA were quantified by ²H and ¹³C NMR analysis of post-mortem liver glycogen and triglyceride. These data were applied to a metabolic model covering glucose-6-P, PPP, triose-P, and de novo lipogenesis (DNL) fluxes. The glucose supplement was converted to glucose-6-P via the direct pathway, while the fructose supplement was metabolized by the liver to gluconeogenic triose-P via fructokinase–aldolase–triokinase. Glucose-6-P from all carbohydrate sources accounted for 40–60% of lipogenic acetyl-CoA and 10–12% was oxidized by the pentose phosphate pathway (PPP). The yield of NADPH from PPP flux accounted for a minority (~30%) of the total DNL requirement. In conclusion, this approach integrates measurements of glucose-6-P, PPP, and DNL fluxes to provide a holistic and informative assessment of hepatic glucose and fructose metabolism.