title: Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-associated metabolic complications.
abstract: Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m(2)). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depot-specific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. katherine.pinnick@ocdem.ox.ac.uk fredrik.karpe@ocdem.ox.ac.uk.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Pinnick
authors.affiliation: Department of Statistics, University of Oxford, Oxford, U.K. Medical Research Council Harwell, Harwell Science and Innovation Campus, Harwell, U.K.
authors.forename: George
authors.initials: G
authors.lastname: Nicholson
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, U.K.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Manolopoulos
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Siobhán E
authors.initials: SE
authors.lastname: McQuaid
authors.affiliation: Institut des Maladies Metaboliques et Cardiovasculaires, INSERM-Université Paul Sabatier, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Keith N
authors.initials: KN
authors.lastname: Frayn
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Nathan
authors.initials: N
authors.lastname: Denton
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, Gentofte, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Department of Statistics, University of Oxford, Oxford, U.K.
authors.forename: Chris C
authors.initials: CC
authors.lastname: Holmes
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D002318:Cardiovascular Diseases / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D012307:Risk Factors; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism
chemical_list: D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5