Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice

Abstract

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

Imipramine Accelerates Nonalcoholic Fatty Liver Disease, Renal Impairment, Diabetic Retinopathy, Insulin Resistance, and Urinary Chromium Loss in Obese Mice

“…We examined glucose levels, lipid metabolism, and oxidative stress, and then we explored the effects of these on the kidneys caused by abnormal metabolism, particularly related to chromium; this topic is little understood. Chromium is involved in normal lipid, protein, and carbohydrate metabolism and can benefit individuals with diabetes, glucose intolerance, obesity, or nephropathy [22]. These results provide a deeper insight into metabolic impacts and the mechanisms of fatty liver as well as kidney damage stemming from chronic imipramine use as an antipsychotic in humans or animals.…”

“…After 7 weeks of the imipramine or saline protocol, we performed an IPGTT on mice with an obesity-like status that were starved overnight but had ad libitum water. The concentration used for the assay was 1 g of glucose per 1 kg of body weight; in animal obesity and diabetes models, this is appropriate for examining antidiabetes activity [22,43]. Blood glucose levels were determined 0, 30, 60, 90, and 120 min after intraperitoneal glucose was administered.…”

“…We analyzed the antioxidant system's functional activity to determine the enzymatic activity of glutathione peroxidase (GPx), hepatic catalase (CAT), and superoxide dismutase (SOD). Ice-cold saline (0.9% sodium chloride) was used to perfuse kidneys, after which they underwent homogenization in chilled potassium chloride (1.17%) by means of a homogenizer and in accordance with a previous description [22]. Next, the homogenates were gathered for analysis after 5 min of centrifugation at 800× g (4 • C).…”

“…How patients with fatty liver further develop nonalcoholic steatohepatitis is complicated; the mechanism could involve various factors such as the overproduction of reactive oxygen species, lowered reactive oxygen species (ROS) detoxification, and heightened profibrogenic and proinflammatory cytokine release [21]. In addition, tricyclic antidepressants may have adverse health effects associated with kidney damage, diabetes, and FLD, and their prolonged use may impede weight control and aggravate diabetes [22].…”

Synergistic anti-obesity effects of red cabbage and chromium administration on obese rats

“…Some animals and clinical studies proved that chromium has a positive significant effect in reducing body weight (Pittler et al, 2003). Chromium is essential cofactor to enhance the effects of insulin on target tissues and inhibit increase in inflammatory markers and oxidative stress levels in cultured monocytes exposed to high glucose levels (Jain et al, 2007, Jain et al, 2010and Chang et al, 2021.…”