Aim: This study aimed to evaluate and compare the therapeutic effects of resmetirom, semaglutide, and obeticholic acid (OCA) on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis progression across three distinct metabolic dysfunction-associated steatohepatitis (MASH) models. A secondary objective was to assess model-specific variations in drug efficacy to inform future preclinical model selection for MASH research. Methods: The Gubra-Amylin NASH (GAN) diet-induced obesity (DIO)-MASH model was induced by the GAN diet in C57BL/6 mice for 24 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. The ob/ob-MASH model was induced by the GAN diet in ob/ob mice for 6 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. GAN-carbon tetrachloride (CCL4) MASH model was induced by 10 weeks of GAN diet and followed by 4 weeks of CCL4 in C57BL/6 mice, resmetirom and OCA were given in the last 4 weeks. Body weights, serum biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids], histopathological NAS scores, fibrosis staging, and α-smooth muscle actin (α-SMA) expression were analyzed. Results: In the GAN DIO-MASH model, both semaglutide and resmetirom reduced NAS significantly, and resmetirom but not semaglutide reduced α-SMA expression. In the ob/ob MASH model, treatment with semaglutide and resmetirom reduced NAS. Semaglutide significantly reduced α-SMA expression. In the GAN-CCL4 MASH model, both resmetirom and OCA significantly reduced MASH progression, resmetirom reduced liver fibrosis and α-SMA expression while OCA reduced α-SMA expression only. Conclusions: Resmetirom, semaglutide, and OCA exhibited model-dependent efficacy in attenuating MASH progression. Although all agents improved the NAS, their antifibrotic effects diverged significantly: resmetirom demonstrated pan-model efficacy, semaglutide selectively reduced α-SMA expression in leptin-deficient models, and OCA showed minimal impact on fibrosis biomarkers. These observations highlight the critical importance of preclinical model selection for MASH therapeutic development, particularly when assessing fibrosis-targeted interventions.

Obesity is a multifactorial disease linked to many comorbidities and has an impact on brain health. It is also known that obesity disrupts the endocannabinoid (eCB) system in the central nervous system and in the periphery, which complicates the underlying mechanisms behind obesity. However, weight loss through lifestyle interventions or bariatric surgery may alleviate obesity-related comorbidities, as well as restore eCB tone. Several studies have reported a decrease in circulating eCBs following weight loss, likely due to the positive association of these mediators with fat mass. However, further research is needed to clarify whether this reduction is a consequence of weight loss or plays a role in facilitating it. This review explores changes in circulating eCBs following weight loss and their potential roles in cerebral homeostasis and the reward system. It examines how lifestyle modifications and bariatric surgery may influence central eCB signalling and contribute to long-term weight loss success. Understanding the mechanisms behind improved brain function after weight loss could provide insights into optimizing obesity treatments.

Aim: Current diabetes guidelines recommend people with gestational diabetes mellitus (PwGDM) use primarily blood glucose meters (BGM) for diabetes management. We evaluated glycemic trends and guideline-recommended glycemic targets achieved in PwGDM using a diabetes app with a family of Bluetooth® connected BGMs. Methods: Anonymized glucose and app analytics data from 26,382 PwGDM were sourced from a server. Data from their first 7-days using the app with connected BGMs was compared to 7-days prior to a 10-week timepoint. Results: Percent fasting readings in range (RIR, < 5.3 mmol/L) improved by +20.3 percentage points in the overall population. Improved glucose RIR (3.5 to 7.8 mmol/L) (+8.3 percentage points), mean blood glucose (BG, –0.59 mmol/L), and fasting RIR (+33.2 percentage points) were observed in those with baseline mean BG ≥ 6.1 mmol/L. Improvements in mean BG of –0.32 to –2.36 mmol/L, and RIR of +3.0 to +38.3 percentage points correlated with higher baseline mean BG ≥ 6.1 to ≥ 7.8 mmol/L. Only 58.5% of PwGDM with baseline mean BG ≥ 6.1 mmol/L had > 80% RIR at baseline, which improved to 79.5% at 10 weeks. PwGDM averaged 17 app sessions and 90 minutes per week on the app. Conclusions: PwGDM engaged with the diabetes app and connected BGM, facilitating attainment of glycemic targets, an especially important outcome for those with higher mean glucose at baseline.