Cover Story Current Issue
Consuming small amounts of palatable food, i.e., snacking, at various times of the day is a highly prevalent behavior in most modern societies. Chronic rest-phase food intake – especially of high-caloric items – promotes obesity and disrupts endogenous circadian rhythms. Notably, humans and mice are more prone to hedonically driven eating behavior, the overconsumption of palatable food, during the late active/early inactive phase, i.e., the morning in mice, the evening in humans. While the effects of calorie-dense food items in promoting body weight gain are well documented, the metabolic impact of snack timing is far less understood.
Kimberly Begemann, Isabel Heyde, Pia Witt, Julica Inderhees, ... Henrik Oster
Current Issue
A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice
Objectives
Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease that can range from hepatic steatosis to non-alcoholic steatohepatitis (NASH), which can lead to fibrosis and cirrhosis. Recently, ketogenic diet (KD), a low carbohydrate diet, gained popularity as a weight-loss approach, although it has been reported to induce hepatic insulin resistance and steatosis in animal model systemsvia an undefined mechanism. Herein, we investigated the KD metabolic benefits and its contribution to the pathogenesis of NASH.
Methods
Using metabolic, biochemical and omics approaches, we identified the effects of a KD on NASH and investigated the mechanisms by which KD induces hepatic insulin resistance and steatosis.
Results
We demonstrate that KD can induce fibrosis and NASH regardless of body weight losscompared to high-fat diet (HFD) fed mice at thermoneutrality. At ambient temperature (23 °C), KD-fed mice develop a severe hepatic injury, inflammation, and steatosis. In addition, KD increases liver cholesterol, IL-6, and p-JNK and aggravates diet induced-glucose intolerance and hepatic insulin resistance compared to HFD. Pharmacological inhibition of IL-6 and JNK reverses KD-induced glucose intolerance, and hepatic steatosis and restores insulin sensitivity.
Conclusions
Our studies uncover a new mechanism for KD-induced hepatic insulin resistance and NASH potentially via IL-6-JNK signaling and provide a new NASH mouse model.
A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice
Objectives
Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease that can range from hepatic steatosis to non-alcoholic steatohepatitis (NASH), which can lead to fibrosis and cirrhosis. Recently, ketogenic diet (KD), a low carbohydrate diet, gained popularity as a weight-loss approach, although it has been reported to induce hepatic insulin resistance and steatosis in animal model systemsvia an undefined mechanism. Herein, we investigated the KD metabolic benefits and its contribution to the pathogenesis of NASH.
Methods
Using metabolic, biochemical and omics approaches, we identified the effects of a KD on NASH and investigated the mechanisms by which KD induces hepatic insulin resistance and steatosis.
Results
We demonstrate that KD can induce fibrosis and NASH regardless of body weight losscompared to high-fat diet (HFD) fed mice at thermoneutrality. At ambient temperature (23 °C), KD-fed mice develop a severe hepatic injury, inflammation, and steatosis. In addition, KD increases liver cholesterol, IL-6, and p-JNK and aggravates diet induced-glucose intolerance and hepatic insulin resistance compared to HFD. Pharmacological inhibition of IL-6 and JNK reverses KD-induced glucose intolerance, and hepatic steatosis and restores insulin sensitivity.
Conclusions
Our studies uncover a new mechanism for KD-induced hepatic insulin resistance and NASH potentially via IL-6-JNK signaling and provide a new NASH mouse model.
2021 impact factor: 8.568
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