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

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Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance 140 Diabetes Volume 65, January 2016 Stephan Wueest,1,2 Flurin Item,1,2 Fabrizio C. Lucchini,1,2,3 Tenagne D. Challa,1,2 Werner Müller,4 Matthias Blüher,5 and Daniel Konrad1,2,3 Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance Diabetes 2016;65:140–148 | DOI: 10.2337/db15-0941 Hepatic steatosis and insulin resistance are among the suggests that interleukin-6 (IL-6) contributes to the devel- most prevalent metabolic disorders and are tightly associ- opment of fatty liver disease and hepatic insulin resistance, ated with obesity and type 2 diabetes. However, the theexactroleofIL-6inthepathogenesisofthesedisordersis underlying mechanisms linking obesity to hepatic lipid thesubjectofintensedebate(2–5). IL-6 is secreted by var- accumulation and insulin resistance are incompletely un- ious cells and tissues such as adipocytes, immune cells, and derstood. Glycoprotein 130 (gp130) is the common signal skeletal muscle, thereby modulating metabolism under both transducer of all interleukin 6 (IL-6) cytokines. We provide physiological and pathophysiological conditions (2,6). To ac- evidence that gp130-mediated adipose tissue lipolysis tivate its intracellular signaling pathways, IL-6 either binds to promotes hepatic steatosis and insulin resistance. In obese its membrane-bound receptor (mIL-6R; classic signaling) or mice, adipocyte-specific gp130 deletion reduced basal to its soluble receptor (sIL-6; trans-signaling pathway). Of lipolysis and enhanced insulin’s ability to suppress lipolysis note, mIL-6R is expressed in the liver and immune cells from mesenteric but not epididymal adipocytes. Consis- butisabsentinadipocytes(7).Inturn,thisligand/receptor tently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, complex associates with a homodimer of glycoprotein 130 adipocyte-specific gp130 knockout mice were protected (gp130), which is a common signal transducer protein of all PATHOPHYSIOLOGY from high-fat diet–induced hepatic steatosis as well as IL-6 cytokines (8,9). Subsequently, the Janus kinase/signal – from insulin resistance. In humans, omental but not sub- transducer and activator transcription and extracellular signal cutaneous IL-6 mRNA expression correlated positively with related kinase (ERK) 1/2 pathways are activated (9,10). liver lipid accumulation (r = 0.31, P < 0.05) and negatively with In the liver, chronically elevated circulating IL-6 levels hyperinsulinemic-euglycemic clamp glucose infusion rate have been proposed to induce insulin resistance and (r = 20.28, P < 0.05). The results show that IL-6 cytokine- inflammation in mice (11,12). In contrast, another study induced lipolysis may be restricted to mesenteric white proposed the opposite after finding IL-6 to reduce inflam- adipose tissue and that it contributes to hepatic insulin re- mation and improve insulin sensitivity in the liver (13). sistance and steatosis. Therefore, blocking IL-6 cytokine Therefore, the hepatic derangements associated with ele- signaling in (mesenteric) adipocytes may be a novel ap- vated IL-6 levels as observed in the former studies (11,12) proach to blunting detrimental fat-liver crosstalk in obesity. may be mediated through an indirect effect of IL-6 through, for example, induction of adipose tissue (AT) lipolysis. In- The prevalence of obesity and associated diseases such as deed, IL-6 was shown to induce lipolysis in vivo and in vitro insulin resistance and hepatic steatosis are increasing to (14,15), and a recent study suggested that IL-6 promotes epidemic proportions (1), but the underlying pathological hepatic insulin resistance indirectly through increased free mechanisms are not fully understood. Although evidence fatty acid (FFA) release from AT in rodents (16). Of note, 1Division of Pediatric Endocrinology and Diabetology, University Children’s Received 8 July 2015 and accepted 8 September 2015. Hospital, Zurich, Switzerland This article contains Supplementary Data online at http://diabetes 2 ’ ’ Children s Research Centre, University Children s Hospital, Zurich, Switzerland .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-0941/-/DC1. 3Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, © 2016 by the American Diabetes Association. Readers may use this article as Switzerland long as the work is properly cited, the use is educational and not for profit, and 4Faculty of Life Sciences, University of Manchester, Manchester, U.K. the work is not altered. 5Department of Medicine, University of Leipzig, Leipzig, Germany Corresponding author: Daniel Konrad, [email protected], or Stephan Wueest, [email protected]. diabetes.diabetesjournals.org Wueest and Associates 141 obesity-induced IL-6 increase in other studies was higher in 58% calories from fat, 28% from carbohydrates, and 16% mesentericfatthaninotheradipose depots (17,18), suggest- from protein. All protocols conformed to Swiss animal pro- ing that IL-6–induced AT lipolysis plays a distinct role in tection laws and were approved by the cantonal veterinary visceral fat. In the current study, we sought to determine office in Zurich, Switzerland. 1 – whether ) mesenteric AT is more sensitive to IL-6 induced Glucose Clamp Studies lipolysis than epididymal fat and whether 2)IL-6–induced Glucose clamp studies were performed as previously de- FFA release from (mesenteric) fat contributes to obesity- scribed (23). Clamps were performed in freely moving mice. associated hepatic steatosis and insulin resistance, making fi GIR was calculated once glucose infusion reached a more or use of adipocyte-speci c gp130-depleted mice. less constant rate, with blood glucose levels at 5 mmol/L (80–90minafterthestartofinsulininfusion).Thereafter, RESEARCH DESIGN AND METHODS blood glucose level was kept constant at 5 mmol/L for 15– Determination of Total Liver Fat and AT IL-6 mRNA 20 min, and GIR was calculated. The glucose disposal rate 3 Expression in Humans was calculated by dividing the rate of [3- H]glucose infusion 3 fi IL-6 mRNA expression was measured in abdominal omental by the plasma [3- H]glucose-speci c activity (24,25). Endog- and subcutaneous AT samples obtained in parallel from 63 enous glucose production (EGP) during the clamp was calcu- men (n =34)andwomen(n = 29) who underwent open lated by subtracting the GIR from the glucose disposal rate fi abdominal surgery for Roux-en-Y bypass, sleeve gastrectomy, (24,25). To assess tissue-speci c glucose uptake, a bolus 14 explorative laparotomy, or elective cholecystectomy. Liver and (10 mCi) of 2-[1- C]deoxyglucose was administered through AT biopsy specimens were taken during surgery, immediately a catheter at the end of the steady-state period. Blood was snap-frozen in liquid nitrogen, and stored at 280°C until sampled 2, 15, 25, and 35 min after bolus delivery. Area 14 further preparations. Measurement of total body and liver under the curve of disappearing plasma 2-[1- C]deoxyglucose fat, tissue sample handling, and analysis of blood samples, was used together with tissue concentration of phosphory- 14 including measurement of serum adiponectin and leptin con- lated 2-[1- C]deoxyglucose to calculate glucose uptake. centrations, was performed as previously described (19,20). Lipolysis Assays IL-6 plasma concentrations were measured by a high-sensi- Adipocytes were isolated and lipolysis assessed as pre- tivity Human IL-6 Quantikine ELISA Kit (R&D Systems, Ox- viously described (26). Isolated adipocytes were incubated ford, U.K.). Insulin sensitivity was assessed with the in the absence or presence of 100 nmol/L insulin, 100 ng/mL hyperinsulinemic-euglycemic clamp method using a previously recombinant murine IL-6 (R&D Systems), or 1 mmol/L described protocol (21). Glucose infusion rate (GIR) was cal- isoproterenol (Sigma, Buchs, Switzerland) for 1 h. FFA culated from the last 45 min of the clamp during which it levels were measured using the ACS-ACOD-MEHA method could be kept constant to achieve the target plasma glucose (Wako Chemicals GmbH, Neuss, Germany). 6 concentration of 5.5 ( 5%) mmol/L. Therefore, the duration Cell Size Determination of the clamp varied among individuals (range 120–200 min). Cell size of isolated adipocytes was analyzed by a Multi- GIR was normalized to lean body mass. In premenopausal sizer 3 Coulter Counter as previously described (27). women, clamp studies were performed during the luteal phase of the menstrual cycle. All participants gave written Blood Sampling informed consent before taking part in the study. All inves- Mouse abdominal cavity was opened immediately after kill, tigations were approved by the ethics committee of the Uni- and the portal vein was exposed. The portal vein was 3 versity of Leipzig (363-10-13122010 and 017-12-230112) and punctured by a syringe (0.30 mm [30G] 8 mm; BD, were carried out in accordance with the Declaration of Helsinki. Franklin Lakes, NJ), and the blood was collected. Systemic Human IL-6 mRNA expression was measured by quantita- blood was sampled after cardiac puncture using similar fi tive RT-PCR using an Assay-on-Demand gene expression kit syringes. Blood was added to an Eppendorf tube with a nal (Hs00985639_m1; Applied Biosystems, Darmstadt, Germany), concentration of 5 mmol/L EDTA. After centrifugation, 2 and fluorescence was detected on an ABI PRISM 7000 Se- plasma was stored at 80°C until further processing. quence Detection System (Applied Biosystems). IL-6 mRNA Determination of Plasma Insulin, Triglyceride, and FFA expression
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