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Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.

ABSTRACT: Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.

SUBMITTER: Chaurasia B

PROVIDER: S-EPMC6787918 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.

Chaurasia Bhagirath B Tippetts Trevor S TS Mayoral Monibas Rafael R Liu Jinqi J Li Ying Y Wang Liping L Wilkerson Joseph L JL Sweeney C Rufus CR Pereira Renato Felipe RF Sumida Doris Hissako DH Maschek J Alan JA Cox James E JE Kaddai Vincent V Lancaster Graeme Iain GI Siddique Monowarul Mobin MM Poss Annelise A Pearson Mackenzie M Satapati Santhosh S Zhou Heather H McLaren David G DG Previs Stephen F SF Chen Ying Y Qian Ying Y Petrov Aleksandr A Wu Margaret M Shen Xiaolan X Yao Jun J Nunes Christian N CN Howard Andrew D AD Wang Liangsu L Erion Mark D MD Rutter Jared J Holland William L WL Kelley David E DE Summers Scott A SA

Science (New York, N.Y.) 20190704 6451

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or o ...[more]

PMID: 31273070

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Project description:Menopause is associated with significant hormonal changes that result in increased total body fat and abdominal fat, amplifying the risk for metabolic syndrome and diseases such as diabetes, cardiovascular disease and cancer in postmenopausal women. Intermittent fasting regimens hold significant health benefit promise for obese humans, however, regimens that include extreme daytime calorie restriction or daytime fasting are generally associated with hunger and irritability, hampering long-term compliance and adoption in the clinical setting. Time-restricted feeding (TRF), a regimen allowing eating only during a specific period in the normal circadian feeding cycle, without calorie restriction, may increase compliance and provide a more clinically viable method for reducing the detrimental metabolic consequences associated with obesity.We tested TRF as an intervention in a mouse model of postmenopausal obesity. Metabolic parameters were measured using Clinical Laboratory Animal Monitoring System (CLAMS) and we carried out glucose tolerance tests. We also stained liver sections with oil red O to examine steatosis and measured gene expression related to gluconeogenesis.Preexisting metabolic disease was significantly attenuated during 7 weeks of TRF. Despite having access to the same high fat diet (HFD) as ad libitum fed (ALF) mice, TRF mice experienced rapid weight loss followed by a delayed improvement in insulin resistance and a reduced severity of hepatic steatosis by having access to the HFD for only 8h during their normal nocturnal feeding period. The lower respiratory exchange ratio in the TRF group compared with the ALF group early in the dark phase suggested that fat was the predominant fuel source in the TRF group and correlated with gene expression analyses that suggested a switch from gluconeogenesis to ketogenesis. In addition, TRF mice were more physically active than ALF fed mice.Our data support further analysis of TRF as a clinically viable form of intermittent fasting to improve metabolic health due to obesity.

Dataset Information

Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.

Publications

Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.

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