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Hypertension, or high blood pressure, is a recognized risk factor for the development of atherosclerosis, which is characterized by narrowing and hardening of the arteries and results from the accumulation of fatty calcified plaques on the inner surface of arterial walls. In Western societies, medical attention has become so focused on hypertension and its treatment that, in many cases, blood pressure reduction is considered to be the highest priority health issue, which often is not in the best interests of the patient. Long-term clinical trials have shown that lowering blood pressure benefits some, but not all, patients. Many of the drugs used to reduce blood pressure (such as diuretics and beta blockers) have adverse metabolic side effects, which are often as deleterious as hypertension itself. Hypertension, especially essential hypertension (high blood pressure that is not secondary to some other identifiable cause), often occurs concomitantly with obesity, glucose intolerance (inability to metabolize glucose), hyperinsulinemia (elevated blood levels of insulin), and disorders of lipid (fat) metabolism. Evidence is accumulating that each of these disorders forms part of a so-called atherogenic syndrome (resulting in the development of atherosclerosis). Insulin resistance occurs when the tissues of the body, which ordinarily respond to insulin by taking up glucose, become much less responsive to the effects of this hormone. It has been proposed that insulin resistance may be a common element in all the above-mentioned components of the atherogenic syndrome, and that treatment strategies should not seek to address one symptom in isolation, but rather should take into consideration the metabolic profile of the patient. In other words, the goal of treatment should be to reduce all atherogenic risk factors. This approach would presumably be reflected in increased insulin sensitivity, and a reduced risk of developing atherosclerosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abstract Objectives Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. Methods To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4). Results Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance. Conclusions These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism. Highlights • A comprehensive analysis of Foxo-dependent miRNA. • miRNAs recapitulate the transcriptional effects of Foxo on insulin signaling. • Foxo regulates miRNA transcription during the fasting/refeeding transition. • miR205 regulates insulin sensitivity through a homeostatic loop with Foxo. [ABSTRACT FROM AUTHOR]

Background: The rs73 8409 C —G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPL43; adiponutrin) leads to a missense mutation (Il48M), which is associated with increased liver fat but not insulin resistance. The Il48M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. Objective: We explored whether the rs73 8409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. Design: We recruited 8 subjects who were homozygous for the rs738409 PNPL43 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPIA3 C allele (PNPLA3-14811). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole- body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([2H5]glycerol infusion) were measured before and after the diet. Results: At baseline, fasting serum insulin and C-peptide concentra- tions were significantly lower in the PNPLA3- 148MM group than in the PNPLA3-14811 group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3- 148MM: -3.1 ± 0.5 kg; PNPLA3- 14811: -3.1 ± 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P< 0.001 and by 18% in the PNPLA3- 148II group (P <0.01). Conclusion: Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. [ABSTRACT FROM AUTHOR]