Knock-Down of IL-1Ra in Obese Mice Decreases Liver Inflammation and Improves Insulin Sensitivity

Franck, Niclas; Maris, Michael; Nalbandian, Sarah; Talukdar, Saswata; Schenk, Simon; Hofmann, Hans-Peter; Bullough, David A.; Osborn, Olivia

doi:10.1371/journal.pone.0107487

Cited by 21 publications

(11 citation statements)

References 44 publications

(55 reference statements)

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“…Administration of IL-1Ra to obese mice markedly reduced steatosis and hepatic lipogenic gene expression demonstrating that IL-1β signaling upregulates hepatic lipogenesis in obesity 22. Moreover, IL-1Ra seems to contribute to the development of IR in a mechanism independent of IL-1Ra binding to IL-1R1 23. The pro-atherogenic role of IL-1α and specifically bone marrow-derived IL-1α was reported by us and confirmed by work from another laboratory 4 7 12.…”

Section: Introductionsupporting

confidence: 59%

Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

Almog

Kfir

Levkovich

et al. 2019

BMJ Open Diab Res Care

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ObjectiveWhile extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methodsTo induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis.ResultsAlthough total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.ConclusionsWe demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

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Section: Introductionsupporting

confidence: 59%

Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

Almog

Kfir

Levkovich

et al. 2019

BMJ Open Diab Res Care

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“…Blood glucose was measured at 0, 15, 30, 60, and 90 min after injection, and blood samples were taken at 0 and 10 min to measure glucose-stimulated insulin secretion. Hyperinsulinemic-euglycemic clamps were performed in the sixth week of iG feeding, as previously described (9,26), to quantitate the degree of systemic and tissue-specific insulin sensitivity. Briefly, dual catheters (MRE-025) were implanted in the right jugular vein, tunneled subcutaneously, and exteriorized at the back of the neck.…”

Section: Methodsmentioning

confidence: 99%

The role of dietary fat in obesity-induced insulin resistance

Lackey

Lazaro

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Consumption of excess calories results in obesity and insulin resistance and has been intensively studied in mice and humans. The objective of this study was to determine the specific contribution of dietary fat rather than total caloric intake to the development of obesity-associated insulin resistance. We used an intragastric feeding method to overfeed excess calories from a low-fat diet (and an isocalorically matched high-fat diet) through a surgically implanted gastric feeding tube to generate obesity in wild-type mice followed by hyperinsulinemic-euglycemic clamp studies to assess the development of insulin resistance. We show that overfeeding a low-fat diet results in levels of obesity similar to high-fat diet feeding in mice. However, despite a similar body weight, obese high-fat diet-fed mice are more insulin resistant than mice fed an isocaloric low-fat diet. Therefore, increased proportion of calories from dietary fat further potentiates insulin resistance in the obese state. Furthermore, crossover diet studies revealed that reduction in dietary fat composition improves glucose tolerance in obesity. In the context of the current obesity and diabetes epidemic, it is particularly important to fully understand the role of dietary macronutrients in the potentiation and amelioration of disease.

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“…Obesity has been considered to be a condition of slight chronic inflammation, and interleukins can influence the function of fat cells in diverse ways. Pro-inflammatory interleukins that are increased in obese people, such as TNF-α, IL-1α and IL-6 secreted by type I macrophages, induce undesirable effects leading to cardiovascular complications in patients with obesity [155,156,157,158]. In contrast, in thin subjects and with specific stimuli, it is possible to generate a change in the population of macrophages by increasing the number of anti-inflammatory type II macrophages [159].…”

Section: Role Of Interleukinsmentioning

confidence: 99%

The Beige Adipocyte as a Therapy for Metabolic Diseases

Lizcano

2019

IJMS

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Adipose tissue is traditionally categorized into white and brown relating to their function and morphology. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue more energetically active, with a greater number of mitochondria and energy production in the form of heat. Since adult humans possess significant amounts of active brown fat depots and its mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis. New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Beige adipocyte has recently attracted special interest because of its ability to dissipate energy and the possible ability to differentiate themselves from white adipocytes. The presence of brown and beige adipocyte in human adults has acquired attention as a possible therapeutic intervention for metabolic diseases. Importantly, adult human brown appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as atherosclerosis, arterial hypertension and diabetes mellitus type 2. Because many epigenetics changes can affect beige adipocyte differentiation from adipose progenitor cells, the knowledge of the circumstances that affect the development of beige adipocyte cells may be important to new pathways in the treatment of metabolic diseases. New molecules have emerged as possible therapeutic targets, which through the impulse to develop beige adipocytes can be useful for clinical studies. In this review will discuss some recent observations arising from the unique physiological capacity of these cells and their possible role as ways to treat obesity and diabetes mellitus type 2.

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Knock-Down of IL-1Ra in Obese Mice Decreases Liver Inflammation and Improves Insulin Sensitivity

Cited by 21 publications

References 44 publications

Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

The role of dietary fat in obesity-induced insulin resistance

The Beige Adipocyte as a Therapy for Metabolic Diseases

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