The prevalence of diabetes is rapidly increasing worldwide and is highly associated with the incidence of depression. Pioglitazone, a Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is widely used for treating patients with type 2 diabetes. However, whether pioglitazone alleviates metabolic disorder-related depression and astrocytic deficits remains unclear. Here we showed that 12 weeks of high-fat diet (HFD) feeding (from 8- to 20-week-old) induced not only obesity and insulin resistance, but also depression-like behaviors in mice. Astrocytic activation, a sign closely associated with depression, was also evident in the ventral hippocampus. Four weeks of pioglitazone (10 or 20 mg/kg, daily, from 20- to 24-week-old) treatment alleviated the HFD-induced glucose-metabolic dysfunctions, upregulation of ventral hippocampal GFAP, reduction of the total process lengths and the number of branch points of the ventral hippocampal CA1 GFAP-immunoreactive astrocytes and depressive phenotypes but had no effect on anxiety-like behaviors or hippocampus-related learning and memory in mice. These findings suggest that pioglitazone could be a potential therapeutic agent for metabolic disorders and associated depression.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mood disorders. Long term use of SSRIs is associated with an increased risk of diabetes, but the underlying mechanism(s) remains elusive. E-cadherin-mediated cell-cell adhesion and elevated [Ca²⁺]_i are important for insulin release and pancreatic β cell functions. This study aims to investigate whether a SSRI, fluoxetine (Prozac), induces pancreatic β cell dysfunction through affecting E-cadherin and/or [Ca²⁺]i. Here we show that fluoxetine significantly reduces glucose stimulated insulin secretion (GSIS). MIN6 cells, an established murine immortalized β cell line, form smaller colonies of loosely packed cells with reduced cell-cell contact after fluoxetine treatment. Immunofluorescence staining reveals that fluoxetine increases cytoplasmic accumulation of E-cadherin and reduces the membrane-localized E-cadherin probably due to increase of its endocytosis. Fluoxetine inhibits spreading of β cells on E-cad/Fc coated slides and also disrupts E-cadherin-mediated actin filaments. Additionally, fluoxetine significantly suppresses endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through reduction of ER calcium storage and inhibition of stromal interaction molecule 1 (STIM1) trafficking. These data suggest that exposure to fluoxetine results in impaired β cell functions, occurring in concert with reduction of E-cadherin-dependent cell adhesion and alterations of calcium homeostasis.

Patients with type 2 diabetes mellitus have more risk to develop depression. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), is drug for mood and anxiety disorders. Previous studies showed that FLX could induce weight loss in non-depressed clinically overweight individuals. Although the anti-appetite effect of FLX is well-documented, its potential effects on metabolic abnormalities have not been investigated. In this study, we want to investigate whether FLX could be a therapeutic drug against high fat diet (HFD)-induced metabolic disorder. We generated metabolic disorders and depressed mouse model by feeding HFD for 12 weeks at the age of 8 weeks. Then, mice were intraperitoneally injected once daily with FLX (10 mg/kg or 20 mg/kg) for four weeks. Our results showed that FLX alleviated the HFD-induced metabolic dysfunctions and depressive phenotypes in mice. FLX improved systemic glucose homeostasis, at least in part, by improving visceral white adipose tissue (vWAT) insulin signaling. Moreover, FLX reduced circulating plasma leptin level, and decreased the expression of adipose triglyceride lipase (ATGL) and peroxisome proliferator-activated receptor gamma (PPARγ) in vWAT. Our data revealed that FLX also reduced the triglyceride (TG) accumulation in vWAT. Therefore, these findings suggest that FLX exhibits significant potential on comorbidity of metabolic disorder and depression in mice.

Background: Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine‐to‐inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post‐transcriptional modification of genome‐encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity‐associated NAFLD and sarcopenia remains unclear.Methods: ADAR2^+/+/GluR‐B^R/R mice (wild type [WT]) and ADAR2^−/−/GluR‐B^R/R mice (ADAR2 knockout [KO]) were subjected to feeding with standard chow or high‐fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross‐sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated.Results: ADAR2 KO mice fed with HFD exhibited lower body weight (−7.7%, P < 0.05), lower liver tissue weight (−20%, P < 0.05), reduced liver lipid droplets in concert with a decrease in hepatic triglyceride content (−24%, P < 0.001) and liver injury (P < 0.01). ADAR2 KO mice displayed protection against HFD‐induced glucose intolerance, insulin resistance and dyslipidaemia. Skeletal muscle mass (P < 0.01), muscle strength (P < 0.05), muscle endurance (P < 0.001) and fibre size (CSA; P < 0.0001) were improved in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. Muscle atrophy‐associated transcripts, such as forkhead box protein O1, muscle atrophy F‐box/atrogin‐1 and muscle RING finger 1/tripartite motif‐containing 63, were decreased in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. ADAR2 deficiency attenuates HFD‐induced local liver and skeletal muscle tissue inflammation. ADAR2 deficiency abolished HFD‐induced systemic (P < 0.01), hepatic (P < 0.0001) and muscular (P < 0.001) SAA1 levels. C2C12 myotubes treated with recombinant SAA1 displayed a decrease in myotube length (−37%, P < 0.001), diameter (−20%, P < 0.01), number (−39%, P < 0.001) and fusion index (−46%, P < 0.01). Myogenic markers (myosin heavy chain and myogenin) were decreased in SAA1‐treated myoblast C2C12 cells.Conclusions: These results provide novel evidence that ADAR2 deficiency may be important in obesity‐associated sarcopenia and NAFLD. Increased SAA1 might be involved as a regulatory factor in developing sarcopenia in NAFLD.

Background: The prevalence of diabetes is rapidly increasing worldwide and is highly associated with the incidence of cancers. In order to prevent diabetes, early diagnosis of prediabetes is important. However, biomarkers for prediabetes diagnosis are still scarce. The hedgehog-interacting protein (Hhip) is important in embryogenesis and is known to be a biomarker of several cancers. However, Hhip levels in subjects with diabetes are still unknown. Methods: In total, 314 participants were enrolled and divided into normal glucose tolerance (NGT; n = 75), impaired fasting glucose (IFG; n = 66), impaired glucose tolerance (IGT; n = 86), and newly diagnosed diabetes (NDD; n = 87) groups. Plasma Hhip levels were determined by an ELISA. The association between the Hhip and the presence of diabetes was examined by a multivariate linear regression analysis. Results: There were significant differences in the body mass index, systolic and diastolic blood pressure, fasting plasma glucose (FPG), post-load 2-h glucose, hemoglobin A1c (A1C), C-reactive protein, total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterol levels among the groups. Concentrations of the Hhip were 2.45 ± 2.12, 4.40 ± 3.22, 4.44 ± 3.64, and 6.31 ± 5.35 ng/mL in subjects in the NGT, IFG, IGT, and NDD groups, respectively. In addition, we found that A1C and FPG were independently associated with Hhip concentrations. Using NGT as a reference group, IFG, IGT, and NDD were all independently associated with Hhip concentrations. Conclusions: Hhip was positively associated with prediabetes and type 2 diabetes mellitus.