Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice.

Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51-/-) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51-/-, and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51-/- mice and in ob/ob mice. TDAG51-/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51-/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51-/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease.

Weight-centric treatment of depression and chronic pain.

Background: Depression and chronic pain are two major chronic non-communicable diseases (CNCD). Considering the bidirectional relationship between obesity and CNCD, it is of the utmost importance to understand the effect of medications utilized to treat these diseases on body weight. Methods: This is a clinical review on the effect of medications for depression and chronic pain on body weight. We searched PubMed, Scopus, MEDLINE, and Google Scholar databases for studies on the topic from January 1, 1950 to April 1, 2022 in English language. Additionally, we present expert opinions in the fields of obesity, depression and chronic pain, providing a weight-centric approach to treat depression and chronic pain. Results: Several antidepressant and chronic pain medications are associated with weight gain. Selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidases, mirtazapine and trazodone are common antidepressants that can increase body weight while bupropion is significantly associated with weight loss. Gabapentin and pregabalin are common chronic pain medications that are linked to weight gain. On the other hand, topiramate is associated with significant weight loss. Obesity, depression and chronic pain experts recommend avoiding medications that can increase body weight if another effective alternative is available. Conclusion: By shifting prescribing practices toward a weight-conscious approach (i.e., switching from weight gain medications to weight loss/neutral), it is possible to mitigate the incidence of drug-induced weight gain.

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice.

Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.