scholarly journals Lactational High Fat Diet in Mice Causes Insulin Resistance and NAFLD in Male Offspring Which Is Partially Rescued by Maternal Metformin Treatment

2021 ◽  
Vol 8 ◽  
Author(s):  
Hannah Hafner ◽  
Molly C. Mulcahy ◽  
Zach Carlson ◽  
Phillip Hartley ◽  
Haijing Sun ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Insulin Resistance ◽  
Liver Disease ◽  
High Fat Diet ◽  
Male Offspring ◽  
Hepatic Insulin Resistance ◽  
Lactation Period ◽  
Metformin Treatment ◽  
High Fat ◽  
Pregnancy And Lactation

Maternal metabolic disease and diet during pregnancy and lactation have important implications for the programming of offspring metabolic disease. In addition, high-fat diets during pregnancy and lactation can predispose the offspring to non-alcoholic fatty liver disease (NAFLD), a rising health threat in the U.S. We developed a model of maternal high-fat feeding exclusively during the lactation period. We previously showed that offspring from dams, given lactational high-fat diet (HFD), are predisposed to obesity, glucose intolerance, and inflammation. In separate experiments, we also showed that lactational metformin treatment can decrease offspring metabolic risk. The purpose of these studies was to understand the programming implications of lactational HFD on offspring metabolic liver disease risk. Dams were fed a 60% lard-based HFD from the day of delivery through the 21-day lactation period. A subset of dams was also given metformin as a co-treatment. Starting at weaning, the offspring were fed normal fat diet until 3 months of age; at which point, a subset was challenged with an additional HFD stressor. Lactational HFD led male offspring to develop hepatic insulin resistance. The post-weaning HFD challenge led male offspring to progress to NAFLD with more severe outcomes in the lactational HFD-challenged offspring. Co-administration of metformin to lactating dams on HFD partially rescued the offspring liver metabolic defects in males. Lactational HFD or post-weaning HFD had no impact on female offspring who maintained a normal insulin sensitivity and liver phenotype. These findings indicate that HFD, during the lactation period, programs the adult offspring to NAFLD risk in a sexually dimorphic manner. In addition, early life intervention with metformin via maternal exposure may prevent some of the liver programming caused by maternal HFD.

scholarly journals Lactational Metformin Treatment in Mouse Dams Ameliorates Maternal High-Fat Diet-induced Metabolic Complications in Male Offspring

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Linh V Nguyen ◽  
Khanh V Doan ◽  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Male Offspring ◽  
Lactation Period ◽  
Metformin Treatment ◽  
High Fat ◽  
Metabolic Complications

Maternal obesity/diabetes severely affects the offspring’s metabolism not only during the fetal and early life development but also later on in the childhood and adulthood stages. Recent evidence suggested that maternal metformin treatment during pregnancy and breastfeeding might provide long-term metabolic benefits on offspring’s glucose homeostasis. We employed a mouse model of maternal overnutrition induced by high fat diet (HFD) to investigate whether an early metformin treatment in mouse dams during lactation period attenuates the maternal HFD-induced metabolic complications in male offspring. The results showed that male offspring from metformin-exposed mothers during suckling period displayed lower body weight and decreased white fat contents. Furthermore, these male offspring had lower blood glucose levels, decreased hyperinsulinemia, enhanced glucose tolerance and insulin sensitivity. Moreover, we found that short-term metformin treatment during lactation period in mouse dams solely improved the glucose tolerance of male offspring exposed with high fat diet (HFD) during both in utero and early postnatal stages, which might primarily result from an increase in insulin secretion. However, this metformin treatment in mouse dams was enabled to abolish most of the metabolic complications of the male offspring exposed with HFD during lactation period. Together, these findings suggest that an early intervention in mouse dams by metformin treatment during lactation period may provide long-term metabolic benefits in regulation of male offspring’s glucose homeostasis.

scholarly journals Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet

2016 ◽  
Vol 8 (1) ◽  
Author(s):  
Douglas Mahana ◽  
Chad M. Trent ◽  
Zachary D. Kurtz ◽  
Nicholas A. Bokulich ◽  
Thomas Battaglia ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Gut Microbiome ◽  
High Fat Diet ◽  
High Fat

Triterpenoid-Rich Fraction from Ilex hainanensis Merr. Attenuates Non-Alcoholic Fatty Liver Disease Induced by High Fat Diet in Rats

2013 ◽  
Vol 41 (03) ◽  
pp. 487-502 ◽  
Author(s):  
Wei-Xi Cui ◽  
Jie Yang ◽  
Xiao-Qing Chen ◽  
Qian Mao ◽  
Xiang-Lan Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Liver Disease ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Density Lipoprotein ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Cyp2e1 Expression ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) has become a major challenge to the healthcare system. This study was designed to evaluate the effect of the triterpenoid-rich fraction (TF) from Ilex hainanensis Merr. on NAFLD. Male Sprague-Dawley (SD) rats were fed a normal diet (control) or high fat diet (NAFLD model). After four weeks, the high fat diet group was orally administrated TF (250 mg/kg) for another two weeks. High fat diet fed rats displayed hyperlipidemia and a decline in liver function compared with control. However, administration with TF could effectively improve these symptoms, as demonstrated by decreasing the plasma levels of triglyceride (p <0.05), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.05), alanine transaminase (p < 0.05), aspartate aminotransferase (p < 0.01), liver index (p < 0.05) and insulin resistance index (p < 0.05) while increasing the high-density lipoprotein cholesterol (p < 0.05). Meanwhile, histopathological examination of livers also showed that TF could reduce the incidence of liver lesions induced by high fat diet. Furthermore, TF could alleviate oxidative stress and inflammation status indicated by the decline malondialdehyde and superoxide dismutase levels (p < 0.01, both) and levels of interleukin 6 and tumor necrosis factor-α (p < 0.05). In addition, immunohistochemistry showed TF evidently elevated the peroxisome proliferator-activated receptor (PPARα) expression (p < 0.01), while it diminished the Cytochrome P450 2E1 (CYP2E1) expression (p < 0.01) in liver. These results demonstrate that TF has potential ability to protect liver against NAFLD by regulating lipids metabolism and alleviating insulin resistance, inflammation and oxidative stress. This effect might be associated with regulating PPARα and CYP2E1 expression.

scholarly journals CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

2020 ◽  
Vol 244 (2) ◽  
pp. 353-367 ◽  
Author(s):  
Jiali Liu ◽  
Yue Li ◽  
Xiaoyan Zhou ◽  
Xi Zhang ◽  
Hao Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Inflammatory Response ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Insulin Action ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
High Fat ◽  
Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

Ethno-pharmacological insulin signaling induction of aqueous extract of Syzygium paniculatum fruits in a high-fat diet induced hepatic insulin resistance

2020 ◽  
pp. 113576
Author(s):  
Prabhakar Yellanur Konda ◽  
Vidyasagar Chennupati ◽  
Sreenivasulu Dasari ◽  
Nishesh Sharma ◽  
Muthukumaran Muthulingam ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Aqueous Extract ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat

scholarly journals PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

2018 ◽  
Vol 115 (38) ◽  
pp. E8996-E9005 ◽  
Author(s):  
Brandon M. Gassaway ◽  
Max C. Petersen ◽  
Yulia V. Surovtseva ◽  
Karl W. Barber ◽  
Joshua B. Sheetz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Large Scale ◽  
Kinase Assay ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

scholarly journals Effects of Maternal Resveratrol on Maternal High-Fat Diet/Obesity with or without Postnatal High-Fat Diet

2020 ◽  
Vol 21 (10) ◽  
pp. 3428 ◽  
Author(s):  
Mei-Hsin Hsu ◽  
Jiunn-Ming Sheen ◽  
I-Chun Lin ◽  
Hong-Ren Yu ◽  
Mao-Meng Tiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Cognitive Impairment ◽  
Adult Male ◽  
High Fat Diet ◽  
Dorsal Hippocampus ◽  
Fetal Brain ◽  
Male Offspring ◽  
High Fat ◽  
Peripheral Insulin Resistance

To examine the effects of maternal resveratrol in rats borne to dams with gestational high-fat diet (HFD)/obesity with or without postnatal high-fat diet. We first tested the effects of maternal resveratrol intake on placenta and male fetus brain in rats borne to dams with gestational HFD/obesity. Then, we assessed the possible priming effect of a subsequent insult, male offspring were weaned onto either a rat chow or a HFD. Spatial learning and memory were assessed by Morris water maze test. Blood pressure and peripheral insulin resistance were examined. Maternal HFD/obesity decreased adiponectin, phosphorylation alpha serine/threonine-protein kinase (pAKT), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF) in rat placenta, male fetal brain, and adult male offspring dorsal hippocampus. Maternal resveratrol treatment restored adiponectin, pAKT, and BDNF in fetal brain. It also reduced body weight, peripheral insulin resistance, increased blood pressure, and alleviated cognitive impairment in adult male offspring with combined maternal HFD and postnatal HFD. Maternal resveratrol treatment restored hippocampal pAKT and BDNF in rats with combined maternal HFD and postnatal HFD in adult male offspring dorsal hippocampus. Maternal resveratrol intake protects the fetal brain in the context of maternal HFD/obesity. It effectively reduced the synergistic effects of maternal HFD/obesity and postnatal HFD on metabolic disturbances and cognitive impairment in adult male offspring. Our data suggest that maternal resveratrol intake may serve as an effective therapeutic strategy in the context of maternal HFD/obesity.

scholarly journals Addendum: de Souza Mesquita, L.M., et al. Modulatory Effect of Polyphenolic Compounds from the Mangrove Tree Rhizophora mangle L. on Non-Alcoholic Fatty Liver Disease and Insulin Resistance in High-Fat Diet Obese Mice. Molecules, 2018, 23, 2114

Molecules ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 169
Author(s):  
Leonardo Mendes De Souza Mesquita ◽  
Cíntia Rabelo e Paiva Caria ◽  
Paola Souza Santos ◽  
Caio Cesar Ruy ◽  
Natalia Da Silva Lima ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Polyphenolic Compounds ◽  
Obese Mice ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Mangrove Tree ◽  
Alcoholic Fatty Liver Disease

The authors wish to add the process number in the Acknowledgments section in this paper [...]

Salidroside and Curcumin Formula Prevents Liver Injury in Nonalcoholic Fatty Liver Disease in Rats

2018 ◽  
Vol 17 (5) ◽  
pp. 0-10
Author(s):  
Hong-Shan Li ◽  
Hao Ying ◽  
Zhe-Yun He
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Lipid Deposition ◽  
Model Group ◽  
High Fat ◽  
Nonalcoholic Fatty Liver

Introduction and aim. Salidroside and curcumin (SC) formula could alleviate lipid deposition in high fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the mechanisms are still unknown, and the magnitude of potential therapeutic benefit remains understudied. Material and methods. The rats were treated with high fat diet for 14 weeks to induce NAFLD. The experiment was divided into control, model (NAFLD), SC formula and rosiglitazone groups (n = 7 in each group). Hematoxylin-eosin (H&E) staining was applied to detect liver morphological changes. Biochemical, metabolic indices and inflammation factors in liver tissue and serum were detected. Additionally, the activities of related enzymes were detected by enzyme-linked immunosorbent assay. Results. In the established rat model, typical lipid deposition and liver steatosis were observed. Liver triglyceride, free fatty acids, sera alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, fasting insulin, fasting blood glucose and homeostasis model assessment of insulin resistance were elevated in model group. Liver malondialdehyde was significantly elevated, while superoxide dismutase was significantly decreased in model group, compared with control. Moreover, tumor necrosis factor-α and Interleukin-1 were significantly produced in model group, compared with control. As a mechanism, high fat diet decreased tissue AMP-activated protein kinase (AMPK), phosphorylated AMPK, carnitine palmitoyltransferase 1 and increased inacetyl-CoA carboxylase (ACCase), phosphorylated ACCase. Importantly, these abnormal changes caused by high fat diet were reduced by SC formula administration. Conclusion. SC formula could ameliorate the injury caused by high fat diet. The effect was likely mediated via its influence on insulin resistance, lipid peroxidation injury and AMPK signaling pathway.

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