Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline.

Background/aims: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease's (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health.

Hepatocyte Nuclear Factor 4-α (HNF4α) controls the insulin resistance-induced pancreatic β-cell mass expansion.

Background: Regardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass.

Aim: Based on the fact that (1) HNF4α is crucial for β-cell proliferation, (2) DEX-induced IR promotes β-cell mass expansion, and (3) the stimulation of β-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of β pancreatic cells is dependent on HNF4α.

Methods: We used WildType (WT) and Knockout (KO) mice for HNF4-α, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days.

Excess of glucocorticoids during late gestation impairs the recovery of offspring's β-cell function after a postnatal injury.

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225.

Beneficial effects of physical exercise for β-cell maintenance in a type 1 diabetes mellitus animal model.

New Findings: What is the central question of this study? Type 1 diabetes mellitus (T1D) leads to hyperglycaemia owing to pancreatic β-cell destruction by the immune system. Physical exercise has been shown to have potentially beneficial protective roles against cytokine-induced pancreatic β-cell death, but its benefits are yet to be proved and should be understood better, especially in the islet environment. What is the main finding and its importance? Physical exercise protects against β-cell loss in a well-described animal model for T1D, induced by multiple low doses of streptozotocin.

Central and peripheral effects of physical exercise without weight reduction in obese and lean mice.

To investigate the central (hypothalamic) and peripheral effects of exercise without body weight change in diet-induced obesity (DIO). Twelve-week-old male C57Bl/6 mice received a control (C) or a high-fat diet (H). Half of them had free access to running wheels for 5 days/week for 10 weeks (CE) and HE, respectively).

Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice.

Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. The liver is the major site for insulin degradation, a process mainly coordinated by the insulin-degrading enzyme (IDE). The beneficial effects of taurine conjugated bile acid (TUDCA) on insulin secretion as well as insulin sensitivity have been recently described.

Spontaneous physical activity and mediators of energy homeostasis in the hypothalamus of mice from 4 to 10 months of age.

What is the central question of this study? Is the initial decline of spontaneous physical activity (SPA) in mice related to impaired insulin and leptin signalling or brain-derived neurotrophic factor expression in the hypothalamus? What is the main finding and its importance? We showed that SPA started to decline at an early stage, concomitantly with an impairment of hypothalamic leptin signalling. Consequently, energy expenditure decreased and glucose tolerance worsened. Our results demonstrate the need to counteract the initial decline in SPA to avoid metabolic impairments and indicate the possible involvement of central leptin in the reduction in SPA with age.

Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme.

Objectives: Glucocorticoid treatment induces insulin resistance (IR), which is counteracted by a compensatory hyperinsulinemia, due to increased pancreatic β-cell function. There is evidence for also reduced hepatic insulin clearance, but whether this correlates with altered activity of insulin-degrading enzyme (IDE) in the liver, is not fully understood. Here, we investigated whether hyperinsulinemia, in glucocorticoid-treated rodents, is associated with any alteration in the insulin clearance and activity of the IDE in the liver.

ARHGAP21 prevents abnormal insulin release through actin rearrangement in pancreatic islets from neonatal mice.

Aims: ARHGAP21 is a Rho GTPase-activating protein (RhoGAP) that associates with many proteins and modulates several cellular functions, including actin cytoskeleton rearrangement in different tissues. However, it is unknown whether ARHGAP21 is expressed in pancreatic beta cells and its function in these cells. Herein, we assess the participation of ARHGAP21 in insulin secretion.

Metabolic memory of ß-cells controls insulin secretion and is mediated by CaMKII.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in calcium pulses as a form of "metabolic memory", just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of ß-cells to intervals of high glucose, followed by a 24-h consolidation period to eliminate any acute metabolic effects.