PMID- 27342408 OWN - NLM STAT- MEDLINE DCOM- 20170828 LR - 20181113 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 59 IP - 11 DP - 2016 Nov TI - Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance. PG - 2406-2416 LID - 10.1007/s00125-016-4031-3 [doi] AB - AIMS/HYPOTHESIS: A subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated. METHODS: Adipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application. RESULTS: Despite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARgamma (also known as PPARG) and CEBPalpha (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group. CONCLUSIONS/INTERPRETATION: Obesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus. FAU - Almuraikhy, Shamma AU - Almuraikhy S AD - Anti-Doping Lab Qatar, Sports City Road, P.O. Box 27775, Doha, Qatar. AD - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK. FAU - Kafienah, Wael AU - Kafienah W AD - School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK. FAU - Bashah, Moataz AU - Bashah M AD - Bariatric and Metabolic Surgery, Hamad Medical Corporation, Doha, Qatar. FAU - Diboun, Ilhame AU - Diboun I AD - Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Doha, Qatar. FAU - Jaganjac, Morana AU - Jaganjac M AD - Anti-Doping Lab Qatar, Sports City Road, P.O. Box 27775, Doha, Qatar. FAU - Al-Khelaifi, Fatima AU - Al-Khelaifi F AD - Anti-Doping Lab Qatar, Sports City Road, P.O. Box 27775, Doha, Qatar. FAU - Abdesselem, Houari AU - Abdesselem H AD - Microbiology and Immunology, Weill Cornell Medicine Qatar, Doha, Qatar. FAU - Mazloum, Nayef A AU - Mazloum NA AD - Microbiology and Immunology, Weill Cornell Medicine Qatar, Doha, Qatar. FAU - Alsayrafi, Mohammed AU - Alsayrafi M AD - Anti-Doping Lab Qatar, Sports City Road, P.O. Box 27775, Doha, Qatar. FAU - Mohamed-Ali, Vidya AU - Mohamed-Ali V AD - Anti-Doping Lab Qatar, Sports City Road, P.O. Box 27775, Doha, Qatar. FAU - Elrayess, Mohamed A AU - Elrayess MA AD - Anti-Doping Lab Qatar, Sports City Road, P.O. Box 27775, Doha, Qatar. melrayess@adlqatar.qa. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160624 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (ADIPOQ protein, human) RN - 0 (Adiponectin) RN - 0 (GATA3 Transcription Factor) RN - 0 (GATA3 protein, human) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 0 (PPAR gamma) SB - IM MH - Adipocytes/metabolism MH - Adipogenesis/genetics/*physiology MH - Adiponectin/genetics/metabolism MH - Adult MH - Diabetes Mellitus, Type 2/genetics/metabolism MH - Female MH - GATA3 Transcription Factor/genetics/metabolism MH - Humans MH - In Vitro Techniques MH - Insulin Resistance/genetics/*physiology MH - Interleukin-6/genetics/*metabolism MH - Male MH - Middle Aged MH - Obesity/genetics/*metabolism MH - PPAR gamma/genetics/metabolism PMC - PMC5506102 OTO - NOTNLM OT - Adipogenesis OT - Insulin resistance OT - Insulin sensitivity OT - Interleukin-6 OT - Obesity OT - Subcutaneous fat OT - Type 2 diabetes mellitus COIS- FUNDING: This research was sponsored by QNRF, Grant no. NPRP6-235-1-048 (MAE, WK, MB, MJ and VMA). DUALITY OF INTEREST: The authors declare that there is no duality of interest associated with this manuscript. CONTRIBUTION STATEMENT: SA carried out most of the data acquisition and analysis, helped with drafting the article and approved the final version. WK contributed to SA's supervision and advised on experimental design. MB contributed to the study design and provided samples and information on participants. ID carried out part of the statistical analysis and helped with data interpretation. MJ helped to set up IL-6 assays and participated in data analysis. FK helped with experimental work and design of the experiments. HA and NAM helped with genetic profiling and data interpretation. MA and VMA advised on experimental design. WK, MB, ID, MJ, FK, HA, NAM, MA and VMA critically revised the manuscript and also approved the final version. MAE was lead principle investigator, designed the experiments, supervised progress, analysed data and wrote and approved the final version of the article. MAE is responsible for the integrity of the work as a whole. EDAT- 2016/06/28 06:00 MHDA- 2017/08/29 06:00 PMCR- 2016/06/24 CRDT- 2016/06/26 06:00 PHST- 2016/04/14 00:00 [received] PHST- 2016/06/02 00:00 [accepted] PHST- 2016/06/26 06:00 [entrez] PHST- 2016/06/28 06:00 [pubmed] PHST- 2017/08/29 06:00 [medline] PHST- 2016/06/24 00:00 [pmc-release] AID - 10.1007/s00125-016-4031-3 [pii] AID - 4031 [pii] AID - 10.1007/s00125-016-4031-3 [doi] PST - ppublish SO - Diabetologia. 2016 Nov;59(11):2406-2416. doi: 10.1007/s00125-016-4031-3. Epub 2016 Jun 24.