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Hypertrophic obesity is associated with type 2 diabetes and impaired adipogenesis

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By Ulf Smith, MD, PhD, Professor of Internal Medicine, The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Sahlgrenska Academy, Göteborg ...

By Ulf Smith, MD, PhD, Professor of Internal Medicine, The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden

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Hypertrophic obesity is associated with type 2 diabetes and impaired adipogenesis Hypertrophic obesity is associated with type 2 diabetes and impaired adipogenesis Presentation Transcript

  • Source: www.myhealthywaist.orgHYPERTROPHIC OBESITY ISASSOCIATED WITH TYPE 2 DIABETESAND IMPAIRED ADIPOGENESISUlf Smith, MD, PhDProfessor of Internal Medicine, The Lundberg Laboratory forDiabetes Research, Center of Excellence for Cardiovascular andMetabolic Research, Sahlgrenska Academy, Göteborg University,Göteborg, Sweden
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgFeatures of the Metabolic SyndromeLow-gradeinflammation ProthromboticstateDyslipidemia HypertensionType 2 diabetesCardiovasculardiseaseGenetics +lifestyleInterleukin-6Insulin resistance((
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgAdapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49MacrophagesPreadipocytesAdipocytesIncreased nutrient influxAdipose hypertrophy andhyperplasia allow adiposetissue to growLarger adipocytes secretemacrophage-attractingchemokinesIncreased FFA release by insulinresistant adipocytes activatesmacrophagesChemokinesFree fatty acids (FFA)CytokinesActivated macrophages blockpreadipocyte recruitment and worseninsulin resistance in mature adipocytes,increasing FFA release andmacrophage activationVicious Circle of Adipocyte Hypertrophy, MacrophageRecruitment and Activation
  • Source: www.myhealthywaist.orgHypertrophic Obesity isAssociated With Local andSystemic Inflammation andInsulin Resistance
  • Source: www.myhealthywaist.orgAdapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49Weight loss Increasingadipose tissuestorage capacityOxidation oflipidsStoring of excesslipids in safe formsIncreasing beta cellnumber or functionPositive energybalanceFailure inadipose tissueexpansionIncreased lipidflux to non-adipose organsToxic lipidaccummulation innon-adipose organsBeta cellcompensationLocalinflammationInsulinresistanceIncreased insulindemandBeta cellfailureHyperglycemiaSteps Leading from Positive Energy Balance to Type 2 Diabetes
  • Source: www.myhealthywaist.orgHyperplasia Hypertrophy150010005000Fatcellvolume(pl)Body fat mass (kg)A0 20 40 60 80 100150010005000Fatcellvolume(pl)Body fat mass (kg)B120 0 50 100 150200150500CountMorphology value (pl)C-500 -300 -100 100 300 5001006020100Frequency(%)DMen Women Nonobese Obese504030Adapted from Arner E et al. Diabetes 2010;59:105-9Adipose Morphology
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgClinical Findings in Women With Adipose Hyperplasia orHypertrophyAdapted from Arner E et al. Diabetes 2010;59:105-9Values are mean ± SD. Age was compared by unpaired t-test. Since it was slightly different betweengroups, the remaining values were compared by analysis of covariance with age as cofactor.VariablesHyperplasia(n=254)Hypertrophy(n=218)p valueAge (years) 38 ± 10 40 ± 11 0.01Waist (cm) 100 ± 22 105 ± 19 0.01Waist-to-hip ratio 0.895 ± 0.085 0.924 ± 0.098 0.0005Body mass index (kg/m2) 32.5 ± 9.4 33.1 ± 8.1 0.37Glucose (mmol/l) 5.2 ± 1.4 5.4 ± 1.0 0.12Insulin (mU/l) 10.1 ± 7.8 13.0 ± 7.7 <0.0001HOMA index* 0.25 ± 0.33 0.42 ± 0.29 <0.0001Cholesterol (mmol/l) 4.9 ± 1.0 5.1 ± 1.1 0.033HDL cholesterol (mmol/l) 1.40 ± 0.39 1.28 ± 0.36 0.001Triglycerides (mmol/l) 1.2 ± 0.8 1.5 ± 0.8 0.002Fat cell volume (pl) 555 ± 224 825 ± 209 <0.0001Fat cell number (x1010) 7.9 ± 2.8 5.3 ± 1.7 <0.0001* Log 10 transformed
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Hypertrophic (enlarged adipose cells) obesity is associatedwith a dysregulated adipose tissue with reduced local andsystemic insulin sensitivity irrespective of amount of body fat. These include several markers of reduced cellular PPARactivation (reduced APM, GLUT4, FABP4, etc. andincreased inflammation). Ability to recruit new subcutaneous fat cells in (hyperplastic)obesity protects against the insulin-resistant obesityphenotype (metabolic syndrome).Insulin Resistance, Obesity and the Dysregulated Adipose TissueAPM: adipocyte-specific secretory proteinFABP4: fatty acid binding protein 4GLUT4: glucose transporter type 4PPAR : peroxisome proliferator-activated receptor gamma
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgReduced IRS-1 in AdipocytesCopyright (1997) National Academy of Sciences, U.S.A.Proc Natl Acad Sci U S A 1997;94:4171-5anti-IRS-1anti-p85anti-IRanti-sypC Type 2diabetesType 1diabetesBLOT: IRS-1 BLOT: IRS-1anti-IRS-1 (c-t)anti-IRS-1 (NH2-t)anti-p85C Type 2diabetes← IRS-1← IRS-1← p85anti-IR: insulin receptor antibodyanti-IRS-1: insulin receptor substrate-1 antibodyC: healthy controlIRS-1: insulin receptor substrate-1
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgC Type 2 diabetes Type 1 diabetesBLOT: GLUT4Reduced GLUT4 in AdipocytesC: healthy controlGLUT4: glucose transporter type 4From Smith UUnpublished data
  • Source: www.myhealthywaist.orgLow IRS-1/GLUT4(n=20)Normal IRS-1/GLUT4(n=52)p valueCell size (µg/cell) 0.55 ± 0.03 0.42 ± 0.02 <0.001Body mass index (kg/m2) 25.8 ± 0.6 24.6 ± 0.4 NSWaist-to-hip ratio 0.92 ± 0.02 0.84 ± 0.01 <0.001Markers of impaired differentiation is ~4-times morefrequent in first-degree relatives vs. nongenetic predispositionQuestion: Is impaired adipose cell differentiation with enlarged cells aconsequence of genetic predisposition for type 2 diabetes and associatedwith insulin resistance?Adapted from Carvalho E et al. FASEB J 2001;15:1101-3and Jansson PA et al. FASEB J 2003;17:1434-40GLUT4: glucose transporter type 4IRS-1: insulin receptor substrate-1Enlarged Abdominal Adipose Cells in Individuals With LowIRS-1 Expression
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgLean individualsGenetic predispositionType 2 diabetes Overweight or obesityMeasureYes(n=17)No(n=65)Yes(n=56)No(n=26)Age (years) 38 ± 2 33 ± 1 35 ± 1 32 ± 1Waist circumference (cm) 82 ± 2(*) 79 ± 1 80 ± 1* 77 ± 1BMI (kg/m2) 22.9 ± 0.4 22.4 ± 0.2 22.7 ± 0.2 22.2 ± 0.3Body fat mass (kg) 19 ± 1 18 ± 1 18 ± 1 17 ± 1Fat cell volume (pl) 511 ± 45** 400 ± 19 431 ± 23 407 ± 30Delta value (pl) 64 ± 38** -37 ± 18 -15 ± 21 -18 ± 28HOMA index 1.62 ± 0.24* 1.17 ± 0.08 1.26 ± 0.09 1.26 ± 0.16HDL cholesterol (mmol/l) 1.39 ± 0.10* 1.62 ± 0.05 1.56 ± 0.07 1.60 ± 0.07Apolipoprotein AI (mmol/l) 1.37 ± 0.07 1.48 ± 0.05 1.43 ± 0.05 1.51 ± 0.07Apolipoprotein B (mmol/l) 0.94 ± 0.06(*) 0.82 ± 0.04 0.86 ± 0.04 0.84 ± 0.06Apo B/apo AI 0.72 ± 0.07* 0.57 ± 0.03 0.63 ± 0.04 0.56 ± 0.04Values are mean ± SE. Significances (by t-test) were only calculated between groups with heredity or not fortype 2 diabetes and between groups with heredity or not for overweight or obesity.(*) 0.05<p<0.1, *p<0.05, **p=0.01Comparison of Lean and Overweight Individuals With or Without aGenetic Predisposition for Type 2 Diabetes or Overweight/ObesityAdapted from Arner P et al. PLoS One 2011;6:e18284
  • Source: www.myhealthywaist.orgAdipocyte Hypertrophy, Fatty Liver and Metabolic RiskFactors in South Asians: The Molecular Study ofHealth and Risk in Ethnic Groups (mol-SHARE)Sonia S. Anand, Mark A. Tarnopolsky, Shirya Rashid, Karleen M. Schulze,Dipika Desai, Andrew Mente, Sandy Rao, Salim Yusuf, Hertzel C. Gerstein,and Arya M. SharmaConclusionsSouth Asians have an increased adipocyte area compared to white Caucasians.This difference accounts for the ethnic differences in insulin, HDL cholesterol,adiponectin, and ectopic fat deposition in the liver.Adapted from Anand SS et al. PLoS One 2011;6:e22112
  • Source: www.myhealthywaist.orgAdapted from Anand SS et al. PLoS One 2011;6:e22112N=108 N=791.51.00.50.0p=0.03 p=0.84Age + sex + BMI Age + sex + BMI +adipocyte cell areaHDL cholesterol (mmol/l)EuropeanSouth Asian5.04.54.03.53.0p=0.006 p=0.13Fasting insulin-In (pmol/l)N=101 N=79Age + sex + BMI Age + sex + BMI +adipocyte cell areaN=108 N=7998765p=0.002 p=0.15Adiponectin (µg/ml)Age + sex + BMI Age + sex + BMI +adipocyte cell areaInfluence of Adipose Tissue Characteristics on EthnicDifferences in Adiponectin, Insulin and HDL cholesterol
  • Source: www.myhealthywaist.orgAdapted from Anand SS et al. PLoS One 2011;6:e22112EuropeanSouth AsianLiverfat(%)Age + sex + BMI Age + sex + BMI +adipocyte cellareaN=95 N=74Age + sex + BMI +adipocyte cell area +deep/superficialfat ratioN=55p=0.005p=0.04p=0.3014121086420Influence of Adipose Tissue Characteristics on EthnicDifferences in Liver Fat
  • Source: www.myhealthywaist.orgAdapted from Anand SS et al. PLoS One 2011;6:e22112Superficial subcutaneous adipose tissue Deep subcutaneous adipose tissueExcess energyVisceral depotAdipocyte hyperplasiaExcess energyVisceral fatAdipocyte hypertrophy↓ AdiponectinFatty acid fluxNo liver fatLiver fat accumulationAbnormal response to chronic overnutrition (e.g. in South Asians vs. white Caucasians)No change incardiometabolicfactorsChange incardiometabolicfactors:↑ Insulin↑ Glucose↑ Triglycerides↓ HDL cholesterol↑ C-reactive protein↑ Blood pressureLower Capacity of South Asians to Store Fat in SubcutaneousAdipocytes Compared to White CaucasiansSuperficial subcutaneous adipose tissueDeep subcutaneous adipose tissue
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Genetic predisposition for type 2 diabetes is associatedwith a restricted adipogenesis and, thus, hypertrophicobesity even in the absence of obesity (body mass index). Due to lack of precursor cells to undergoadipogenesis?(Diabetes 2009;58:1550-7) Or inadequate signalling/activation of adipogenesis?Prime candidates: BMP4 induces committment of precursor cells into theadipocyte lineage. Canonical Wnt prevents PPAR activation anddifferentiation of preadipocytes.SummaryBMP4: bone morphogenetic protein 4PPAR : peroxisome proliferator-activated receptor gamma
  • Source: www.myhealthywaist.orgAdapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24Mesenchymalstem cellsMyoblasts OsteoblastsAdipocytesPreadipocytesBMP4Wnt + Wnt +Wnt -Wntβ-catenin+PPARγC/EBPαC/EBPδ/βAdipocyte genesPreadipocytegenesAdipogenicstimuliBMP4: bone morphogenetic protein 4C/EBPα: CCAAT/enhancer binding proteinalphaC/EBPδ/β: CCAAT/enhancer ninding proteindelta/betaPPAR : peroxisome proliferator-activatedreceptor gammaTNF- : tumor necrosis factor-alphaCanonical Wnt Signalling Regulates Mesenchymal Stem Cell FateTNF-+
  • Source: www.myhealthywaist.orgA) Nutritional deprivationAdipocytePreadipocyteAdipogenesisB) OvernutritionAdipocytePreadipocyteAdipogenesisAdipocytehyperplasiaC) Chronic overnutritionHypertrophicadipocytesPreadipocyteAdipogenesisEctopic lipid accumulation(liver and muscle)Adipose tissue inflammationLocal Factors Regulates AdipogenesisAdapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgA Model for the Wnt Activation of the Beta-Catenin SignallingPathway With Wnt SignalLRP FrizzledAxinActivedishevelledAPCInactive GSK-3βStableβ-cateninUnphosphorylated β-cateninmigrates to nucleus anddisplaces grouchoGrouchoTranscriptionLEF-1/TCFWntFrom Smith UUnpublished data
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.orgImpaired Adipogenesis in Hypertrophic ObesityAdapted from Gustafson B & Smith U Diabetes 2012:61;1217-2414012010080Cellsize(µm)Oil Red O (fold change)0 1 2 3 460405
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Is not due to lack of adipogenic precursor cells but toinappropriate inhibitory signalling. BMP4 plays a role for precursor cell commitment anddifferentiation. Wnt activation prevents the effect of BMP4 and isinappropriately activated in hypertrophic obesity.Hypertrophic ObesityBMP4: bone morphogenetic protein 4
  • Source: www.myhealthywaist.orgSource: www.myhealthywaist.org1. Genetic predisposition for type 2 diabetes isassociated with a restricted adipogenesis andhypertrophic obesity.2. The restricted adipogenesis in hypertrophicobesity is not due to lack of precursor cells butto inadequate signalling/activation mainlyinvolving inadequate suppression of canonicalWnt.Conclusions
  • Source: www.myhealthywaist.org