Modulation of Cell-Mediated Immunity to Suppress High Fat Diet-Induced Obesity and Insulin Resistance.

PURPOSE: To assess the effect of immune modulators, cyclosporin A and fingolimod, on high fat diet-induced obesity and insulin resistance. METHODS: C57BL/6 mice were fed a high fat diet and injected intraperitoneally with cyclosporine A, fingolimod, or vehicle twice weekly for 15 weeks. Body weight and food intake were manually measured every other day. Glucose tolerance test, insulin sensitivity, and body composition were examined and compared between the control and the immune modulator treated animals. Tissue samples were collected at the end of the experiment and examined for serum biochemistry, histology, and mRNA levels of marker genes for inflammation, and glucose and lipid metabolism in white and brown adipose tissues and in the liver. RESULTS: Cyclosporine A and fingolimod suppressed high fat diet-induced weight gain, reduced hepatic fat accumulation, and improved insulin sensitivity. The beneficial effects are associated with altered expression of F4/80, Cd68, Il-6, Tnf-α, and Mcp-1 genes, which are involved in macrophage-related chronic inflammation in adipose and hepatic tissues. CONCLUSION: Immune modulation represents an important intervention for obesity and obesity-associated insulin resistance.

Melatonin improves non-alcoholic fatty liver disease via MAPK-JNK/P38 signaling in high-fat-diet-induced obese mice.

BACKGROUND: Melatonin can regulate lipid metabolism, increase insulin sensitivity, regulate glucose metabolism and reduce body weight. This study is aimed to determine the effects and mechanism of action of melatonin on non-alcoholic fatty liver disease (NAFLD) in high-fat-diet (HFD) induced obese mice. METHODS: NAFLD was induced by HFD in C57BL/6 mice. A total of 24 mice were randomly assigned to 4 groups. Groups A and B were fed with HFD for 36 weeks while groups C and D were fed with a regular diet (RD). During the last 12 weeks, Groups A and C were treated with 10 mg/kg melatonin while Groups B and D were treated with water in the same volume by intragastric administration. Body and liver weight, blood glucose, serum transaminases and lipid levels, and markers of hepatic inflammation were measured. Histological analyses were also performed on liver tissue. RESULTS: After 12 weeks of treatment with melatonin, body weights (Group A: before 53.11 ± 0.72 vs after 12w treatment 39.48 ± 0.74) and liver weights (A 1.93 ± 0.09 g vs B 2.92 ± 0.19 g vs C 1.48 ± 0.09 g vs D 1.49 ± 0.10 g), fasting plasma glucose, alanine transaminase (A 24.33 ± 11.90 IU/L vs B 60.80 ± 10.18 IU/L vs C 13.01 ± 3.49 IU/L vs D 16.62 ± 2.00 IU/L), and low-density cholesterol (A 0.24 ± 0.06 mmol/L vs B 1.57 ± 0.10 mmol/L vs C 0.28 ± 0.06 mmol/L vs D 0.29 ± 0.03 mmol/L) were significantly decreased in HFD mice. HFD fed mice treated with melatonin showed significantly less liver steatosis. Treatment of HFD fed mice with melatonin led to a significant decrease in the expression of TNF-α, IL-1ß, and IL-6 measured using quantitative real-time polymerase chain reaction (qRT-PCR). HFD fed mice demonstrated increased phosphorylation of P38 and JNK1/2, which was reduced by melatonin treatment. CONCLUSIONS: The study concluded that melatonin could improve NAFLD by decreasing body weight and reduce inflammation in HFD induced obese mice by modulating the MAPK-JNK/P38 signaling pathway.

Differential patterns of insulin secretion and sensitivity in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease versus patients with type 2 diabetes mellitus alone.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) often coexist and have adverse outcomes. The aim of our study was to elucidate metabolic abnormalities in patients with DM-NAFLD versus those with T2DM alone. METHODS: Patients were divided into two groups: 26 T2DM patients with NAFLD and 26 gender-, age-, and body mass index-matched patients with T2DM alone. Patients took a 75-g oral glucose tolerance test (OGTT), which measured serum insulin and C-peptide (C-p) levels at baseline (0 min), 30 min, 60 min, and 120 min after glucose challenge. RESULTS: Patients with DM-NAFLD or T2DM alone had similar blood glucose levels. ß-cell hypersecretion was more obvious in patients with DM-NAFLD. In addition, fasting, early-phase, and late-phase C-peptide levels were significantly increased in patients with DM-NAFLD (ΔC-p 0-30 min, P < 0.05; Area Under the Curve (AUC) C-p/PG 30-120 min ratio, P < 0.01; and AUC C-p 30-120 min, P < 0.01). Hepatic and extrahepatic insulin resistance during the OGTT did not differ significantly between groups. Hepatic insulin sensitivity independently contributed to the early phase (0-30 min) of the OGTT in patients with T2DM and NAFLD, whereas a significant deficit in late insulin secretion independently contributed to the 30-120 min glucose status in patients with T2DM only. CONCLUSIONS: In patients with similar levels of insulin resistance and hyperglycemia, DM-NAFLD was associated with higher serum insulin levels than T2DM alone. Hyperinsulinemia is caused mainly by ß-cell hypersecretion. The present study demonstrates pathophysiological differences in mechanisms of insulin resistance in patients with DM-NAFLD versus T2DM alone.

Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans.

OBJECTIVE: This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans (AN). METHODS: A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity, glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatonin were measured. RESULTS: After 12 weeks of treatment with melatonin (3 mg/day), homeostasis model assessment insulin resistance index (HOMA-IR) (8.99 ± 5.10 versus 7.77 ± 5.21, p < 0.05) and fasting insulin (37.09 5 ± 20.26 µU/ml versus 32.10 ± 20.29 µU/ml, p < 0.05) were significantly decreased. Matsuda index (2.82 ± 1.54 versus 3.74 ± 2.02, p < 0.05) was significantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight, body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. CONCLUSIONS: It was concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improving insulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095.

Upregulated Pdx1 and MafA Contribute to ß-Cell Function Improvement by Sleeve Gastrectomy.

PURPOSE: Sleeve gastrectomy is an effective technique for the treatment of severe obesity, and its effects on the improved ß-cell function have not yet been fully understood. MATERIALS AND METHODS: From February 2014 to July 2015, sleeve gastrectomy was performed in 5 patients with T2D, who were assessed before and after sleeve gastrectomy (SG). Moreover, a high-fat-diet (HFD) mouse model was also used to study the molecular mechanisms of ß-cell functional improvement after SG. RESULTS: The glucose-stimulated acute insulin response was restored in the T2D patients after SG. The expression of GLP-1 in colonic tissue as well as ß-cell specific transcription factors (TFs), Pdx1, and MafA in islets was significantly increased after SG. CONCLUSION: ß-cell dysfunction can be ameliorated by SG. The re-activation of key TFs contributes to the improvement of ß cell function.

FGF21 Is Associated with Acanthosis Nigricans in Obese Patients.

Objective. We aimed to investigate the relationship between FGF21 and obesity-related acanthosis nigricans (AN). Methods. 40 obese patients without AN (OB group), 40 obese patients with AN (AN group), and 40 healthy volunteers (control group, CON) were included in this study. Weight, BMI, lipid profile, FFA, UA, and CRP were measured in all participants. Oral glucose tolerance tests (OGTT) were performed and serum glucose and plasma insulin were measured. Serum FGF21 was measured by ELISA. Results. Compared with OB group, AN group had higher levels of fasting insulin and homeostasis model of assessment for insulin resistance (HOMA-IR) (P < 0.05), but lower serum levels of blood glucose. The difference of FGF21 among three groups was significant and AN group showed the highest serum level of FGF21 (P < 0.05). Serum FGF21 was most positively correlated with fasting insulin and HOMA-IR. Multiple logistic analysis showed that FGF21 was the independent risk factor for AN (OR 4.550; 95% CI 1.054-19.635; P = 0.042). Conclusion. AN patients had more serious hyperinsulinemia but better serum levels of blood glucose than OB. Increased FGF21 is associated with AN in obese patients and may be considered as compensatory response to the decreased insulin sensitivity.

Preventative Sleeve Gastrectomy Contributes to Maintaining ß Cell Function in db/db Diabetic Mouse.

BACKGROUND: We used the leptin-receptor (LPR)-deficient mice model (db/db), a spontaneous model of type 2 diabetes with early ß cell dysfunction to determine whether a preventative sleeve gastrectomy (SG) is an effective technique for the treatment of ß cell failure. METHODS: The animals operated at an early stage of life, prior to metabolic alterations, were used to study the molecular mechanisms of ß cell function improvement after a SG. RESULTS: ß cell function was significantly increased, and islet morphology remained normal, after the SG. The expression of Glut2, Pdx1, MafA, and Nkx6.1 were significantly increased after the SG. The expression of GLP-1 in the colonic tissue, as well as GLP-1R and PKC in islets, was significantly increased after the SG. CONCLUSIONS: ß cell dysfunction can be ameliorated by a preventative SG for db/db mice. Maintaining the GLP-1 pathway and key transcript factor (TF) activation contributes to the improvement of ß cell function after a preventative SG.

Evaluation of depressive symptoms in obese patients with or without acanthosis nigricans.

OBJECTIVE: Acanthosis nigricans (AN) has been closely associated with obesity. Depression has also been shown to be disproportionally prevalent among obese people. However, there is still a paucity of studies on the relationship between depressive symptoms and AN in obese patients. This study examined the difference in metabolic disorders and depressive symptoms between simple obesity and obesity-related AN. METHODS: A total of 88 obese patients treated in our department were selected for analysis. They were divided into simple obesity (OB n=30) and obesity with acanthosis nigricans (AN n=58). A control (CON) group included 56 normal weight healthy volunteers. The self-administrated Beck Depression Inventory-II questionnaire was used. General characteristics and clinical data were collected for analysis. RESULTS: The frequency of depressive symptoms was recorded as 67.2% in the AN group, 43.4% in the OB group, and 3.6% in the CON group (P <0.001). The severity of depression in the AN group was significantly higher than in the OB group and CON group (P <0.001). Patients with moderate depressive symptoms had higher levels of inflammatory markers than those with mild symptoms depression. Free fatty acid (FFA) and uric acid (UA) level in the AN group were significantly increased compared with the OB group (P=0.010, P=0.020). Discrimination was associated with depressive symptoms (P <0.001). CONCLUSION: Obese patients had a higher risk of depressive symptoms, which were even higher in patients with AN. AN is associated with more depressive symptoms and high inflammation status. Psychological intervention should be started early to prevent further physical and pathological impairment in obese patients, especially obese patients with AN.

Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective.

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.

ATP Synthase ß-Chain Overexpression in SR-BI Knockout Mice Increases HDL Uptake and Reduces Plasma HDL Level.

HDL cholesterol is known to be inversely correlated with cardiovascular disease due to its diverse antiatherogenic functions. SR-BI mediates the selective uptake of HDL-C. SR-BI knockout diminishes but does not completely block the transport of HDL; other receptors may be involved. Ectopic ATP synthase ß-chain in hepatocytes has been previously characterized as an apoA-I receptor, triggering HDL internalization. This study was undertaken to identify the overexpression of ectopic ATP synthase ß-chain on DIL-HDL uptake in primary hepatocytes in vitro and on plasma HDL levels in SR-BI knockout mice. Human ATP synthase ß-chain cDNA was delivered to the mouse liver by adenovirus and GFP adenovirus as control. The adenovirus-mediated overexpression of ß-chain was identified at both mRNA and protein levels on mice liver and validated by its increasing of DiL-HDL uptake in primary hepatocytes. In response to hepatic overexpression of ß-chain, plasma HDL-C levels and cholesterol were reduced in SR-BI knockout mice, compared with the control. The present data suggest that ATP synthase ß-chain can serve as the endocytic receptor of HDL, and its overexpression can reduce plasma HDL-C.