Template to improve glycemic control without reducing adiposity or dietary fat

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

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Pycnogenol protects against diet-induced hepatic steatosis in apolipoprotein-E-deficient mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00009.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E218-E228 ◽

Cited By ~ 2

Author(s):

Difei Wang ◽

Huiying Cong ◽

Xiaoli Wang ◽

Yanli Cao ◽

Shoichiro Ikuyama ◽

...

Keyword(s):

Lipid Metabolism ◽

Apolipoprotein E ◽

Hepatic Steatosis ◽

Inflammatory Cytokines ◽

Lipid Content ◽

Acid Uptake ◽

Short Term Treatment ◽

Hepatic Lipid ◽

Deficient Mice ◽

Hepatic Lipid Content

PycnogenolR (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg·kg−1·day−1 for 2 wk in advance and were then fed a high-cholesterol and -fat diet (HCD) for 8 wk. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for nonalcoholic fatty liver disease (NAFLD).

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Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. E244-E252 ◽

Cited By ~ 30

Author(s):

Terry D. Hinds ◽

Peter A. Hosick ◽

Shujuan Chen ◽

Robert H. Tukey ◽

Michael W. Hankins ◽

...

Keyword(s):

Hepatic Steatosis ◽

Lipid Content ◽

Transcriptional Activity ◽

Fasting Blood Glucose ◽

Humanized Mice ◽

Gilbert’S Syndrome ◽

Hepatic Lipid ◽

Insulin Levels ◽

Gilbert's Syndrome ◽

Hepatic Lipid Content

Gilbert’s syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-α (PPARα). Additionally, we have shown that serine 73 phosphorylation [Ser(P)73] of PPARα decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert’s polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert’s mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARα regulated genes as well as immunostaining of Ser(P)73 PPARα from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P)73 PPARα immunostaining in livers and increased PPARα transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P)73 PPARα, causing an increase in PPARα transcriptional activity.

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Comment on “Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women”

Science ◽

10.1126/science.abj1696 ◽

2021 ◽

Vol 373 (6554) ◽

pp. eabj1696

Author(s):

Charles Brenner

Keyword(s):

Placebo Group ◽

Insulin Sensitivity ◽

Randomized Trial ◽

Lipid Content ◽

Liver Fat ◽

Hepatic Lipid ◽

Nicotinamide Mononucleotide ◽

Hepatic Lipid Content

Yoshino et al. (Reports, 11 June 2021, p. 1224) have reported that nicotinamide mononucleotide (NMN) increases muscle insulin sensitivity in prediabetic women. However, the 13 women who received NMN had hepatic lipid content of 6.3 ± 1.2%, whereas the 12 in the placebo group had 14.8 ± 2.0% (P = 0.003). Given that a target of NMN is liver fat clearance, this was not an effectively randomized trial.

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Hypoglycemic Effect of Vitexin in C57BL/6J Mice and HepG2 Models

Journal of Food Quality ◽

10.1155/2021/5535476 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Weidong Xu ◽

Jiayao Li ◽

Weipeng Qi ◽

Ye Peng

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Weight Gain ◽

Blood Glucose ◽

Glucose Uptake ◽

Lipid Content ◽

Hepg2 Cells ◽

Body Weight Gain ◽

Tnf Α ◽

Hepatic Lipid Content

Apigenin-8-C-glucoside (vitexin), a natural phytochemical contained in hawthorn, has been reported to have versatile beneficial bioactivities, such as antioxidation, anticancer property, and adipogenesis inhibition. The present research aimed to determine the influence of vitexin on insulin resistance elicited by HFD in mice and HepG2 cells. Vitexin markedly alleviated body weight gain and improved glucose and insulin intolerance induced by HFD. Vitexin partially normalized blood glucose, cholesterol, TNF-α, and hepatic lipid content. Moreover, vitexin recovered the reduced glucose uptake induced by glucosamine. The present results indicate that vitexin prevents HFD-induced insulin resistance.

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Diagnostic performance of cytology for assessment of hepatic lipid content in dairy cattle

Journal of Dairy Science ◽

10.3168/jds.2017-12897 ◽

2018 ◽

Vol 101 (2) ◽

pp. 1379-1387 ◽

Cited By ~ 4

Author(s):

M.M. Fry ◽

B. Yao ◽

C. Ríos ◽

C. Wong ◽

S. Mann ◽

...

Keyword(s):

Dairy Cattle ◽

Lipid Content ◽

Diagnostic Performance ◽

Hepatic Lipid ◽

Hepatic Lipid Content

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Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes

10.2337/figshare.12315737.v1 ◽

2020 ◽

Author(s):

Oana P. Zaharia ◽

Klaus Strassburger ◽

Birgit Knebel ◽

Yuliya Kupriyanova ◽

Yanislava Karusheva ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Lipid Content ◽

Whole Body ◽

Hepatic Lipid ◽

Insulin Resistant ◽

Increased Risk ◽

Glucose Tolerant ◽

Hepatic Lipid Content

<a>Objective</a>: The rs738409(G) single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently-described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (HCL) and insulin sensitivity in recent-onset diabetes mellitus. Research Design and Methods: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy. Results: The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001). Conclusions: Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.

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