Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance

Wueest, Stephan; Item, Flurin; Lucchini, Fabrizio C.; Challa, Tenagne D.; Müller, Werner; Blüher, Matthias; Konrad, Daniel

doi:10.2337/db15-0941

Cited by 85 publications

(74 citation statements)

References 57 publications

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“…No studies have measured overfeeding effects on lipolysis in humans. High saturated fat-feeding in mice stimulates lipolysis via inflammatory mediators (6). In keeping with such data, we found upregulation of multiple inflammationrelated pathways in the adipose tissue transcriptome.…”

Section: Pathways Of Ihtgsupporting

confidence: 87%

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Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

et al. 2018

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OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

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Section: Pathways Of Ihtgsupporting

confidence: 87%

“…Excess sugar intakes increase DNL and IHTG content in humans (5). In mice, a high-fat diet increases adipose tissue lipolysis (6). The pathway by which IHTGs are synthesized in response to overconsuming fat has not been studied in humans.…”

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confidence: 99%

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

et al. 2018

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“…Visceral fat cells in vitro have increased lipid synthesis and lipolysis compared to abdominal subcutaneous adipocytes, findings that have been corroborated in vivo in short-term experimental settings678. As vWAT is drained by the portal vein, increased levels of portal fatty acids may cause liver-associated metabolic complications, such as hepatic steatosis and/or hepatic insulin resistance, in the overweight and obese states9101112.…”

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confidence: 89%

Impact of fat mass and distribution on lipid turnover in human adipose tissue

et al. 2017

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Differences in white adipose tissue (WAT) lipid turnover between the visceral (vWAT) and subcutaneous (sWAT) depots may cause metabolic complications in obesity. Here we compare triglyceride age and, thereby, triglyceride turnover in vWAT and sWAT biopsies from 346 individuals and find that subcutaneous triglyceride age and storage capacity are increased in overweight or obese individuals. Visceral triglyceride age is only increased in excessively obese individuals and associated with a lower lipid removal capacity. Thus, although triglyceride storage capacity in sWAT is higher than in vWAT, the former plateaus at substantially lower levels of excess WAT mass than vWAT. In individuals with central or visceral obesity, lipid turnover is selectively increased in vWAT. Obese individuals classified as ‘metabolically unhealthy' (according to ATPIII criteria) who have small subcutaneous adipocytes exhibit reduced triglyceride turnover. We conclude that excess WAT results in depot-specific differences in lipid turnover and increased turnover in vWAT and/or decreased turnover in sWAT may result in metabolic complications of overweight or obesity.

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“…8,9 Rytka et al found that mice receiving a portal drained fat transplant, similar to MAT, had worse hepatic insulin resistance compared to mice receiving vena cava drained fat. 10 Mesenteric adipose tissue inflammation contributes to NAFLD, but what promotes MAT inflammation is still not clear. 10 Mesenteric adipose tissue inflammation contributes to NAFLD, but what promotes MAT inflammation is still not clear.…”

Section: Introductionmentioning

confidence: 99%

Mesenteric adipose tissue B lymphocytes promote local and hepatic inflammation in non‐alcoholic fatty liver disease mice

Tan

et al. 2019

J Cellular Molecular Medi

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Mesenteric adipose tissue (MAT) inflammation is associated with non‐alcoholic fatty liver disease (NAFLD), and immune cells play pivotal roles in the inflammation of adipose tissue. Here, we investigated the roles of MAT B lymphocytes in NAFLD. Mice fed with high‐fat diet (HFD) and normal diet (ND) were killed in time gradients (4, 8 and 12 weeks). Compared with ND‐fed mice, intra‐hepatic CD45 + CD19 + B lymphocytes increased after 4 weeks ( P < 0.01) of HFD feeding, and lasted until the 12th week, infiltrated earlier than CD45 + CD3 + T lymphocytes and CD45 + F4/80 + macrophages. The mRNA expression of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and monocyte chemotactic protein (MCP)‐1 decreased in MAT of B null HFD‐fed mice compared to that in wild‐type HFD‐fed mice, along with lesser macrophages. Mesenteric adipose tissue B cells from HFD‐fed mice promoted macrophage differentiation to type‐Ι macrophages and expression of pro‐inflammatory cytokines in vitro. Macrophages pre‐treated with MAT B cells from HFD‐fed mice showed elevated mRNA expression of IL‐6 and TNF‐α and declined IL‐10 levels in adipocytes compared to ND MAT B cell pre‐treated macrophages. Besides, internal near‐infrared scanning and external transwell assay showed that HFD MAT B cells migrated to the liver more than ND MAT B cells. High‐fat diet MAT B cells induced higher MCP‐1 and lower IL‐10 expression in primary hepatocytes compared to ND MAT B cells in co‐culture experiment. These data indicate that B lymphocytes infiltrate early in MAT during the development of NAFLD, which may not only promote MAT inflammation by regulating macrophages but also migrate to the liver and induce hepatocytes inflammation.

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Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance

Cited by 85 publications

References 57 publications

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

Impact of fat mass and distribution on lipid turnover in human adipose tissue

Mesenteric adipose tissue B lymphocytes promote local and hepatic inflammation in non‐alcoholic fatty liver disease mice

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