João Victor Esteves

Maternal physical activity enhances offspring metabolic resilience, whereas prenatal psychosocial stress predisposes offspring to lifelong metabolic dysfunction. Whether maternal exercise can attenuate the deleterious programming effects of stress has remained unclear. Here, we investigated the effect of maternal exercise and/or prenatal psychosocial stress on the metabolic health of male and female offspring. C57BL/6 dams were assigned to four conditions: sedentary/non‐stressed (SED‐NS), sedentary/stressed (SED‐S), exercised/non‐stressed (EX‐NS), or exercised/stressed (EX‐S). Male EX‐NS offspring had improved glucose tolerance compared to SED‐NS and SED‐S; however these effects were blunted in male EX‐S offspring, indicating that prenatal stress abolished this exercise‐induced benefit. In contrast, there was no effect of maternal stress or exercise on glucose tolerance in female offspring. Maternal exercise chronically elevated basal corticosterone in male offspring, regardless of maternal stress. Maternal stress increased mineralocorticoid receptor ( Nr3c2 ) mRNA and glucocorticoid receptor (NR3C1) protein expression in brown adipose tissue in male mice, while exercise restored NR3C1 expression. These findings indicate that prenatal stress blunts the metabolic benefits of maternal exercise in male offspring and is associated with altered corticosteroid signaling in brown adipose tissue. Together, the data identify a stress–exercise interaction that may influence offspring metabolic programming through tissue‐specific regulation of glucocorticoid pathways.

Metabolic diseases, notably obesity and type 2 diabetes (T2D), have reached alarming proportions and constitute a significant global health challenge, emphasizing the urgent need for effective preventive and therapeutic strategies. In contrast, exercise training emerges as a potent intervention, exerting numerous positive effects on metabolic health through adaptations to the metabolic tissues. Here, we reviewed the major features of our current understanding with respect to the intricate interplay between metabolic diseases and key metabolic tissues, including adipose tissue, skeletal muscle, and liver, describing some of the main underlying mechanisms driving pathogenesis, as well as the role of exercise to combat and treat obesity and metabolic disease.

Purpose: NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression. Methods: Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week. Results: T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P< 0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered. Conclusion: NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.

Materials and Methods Description; Manuscript David-Silva et al protocol (method) by Joao Victor Esteves