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 University, Göteborg, Sweden

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Hypertrophic obesity is associated with type 2 diabetes and impaired adipogenesis

  1. 1. Source: www.myhealthywaist.org HYPERTROPHIC OBESITY IS ASSOCIATED WITH TYPE 2 DIABETES AND IMPAIRED ADIPOGENESIS 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
  2. 2. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Features of the Metabolic Syndrome Low-grade inflammation Prothrombotic state Dyslipidemia Hypertension Type 2 diabetes Cardiovascular disease Genetics + lifestyle Interleukin-6 Insulin resistance ( (
  3. 3. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49 Macrophages Preadipocytes Adipocytes Increased nutrient influx Adipose hypertrophy and hyperplasia allow adipose tissue to grow Larger adipocytes secrete macrophage-attracting chemokines Increased FFA release by insulin resistant adipocytes activates macrophages Chemokines Free fatty acids (FFA) Cytokines Activated macrophages block preadipocyte recruitment and worsen insulin resistance in mature adipocytes, increasing FFA release and macrophage activation Vicious Circle of Adipocyte Hypertrophy, Macrophage Recruitment and Activation
  4. 4. Source: www.myhealthywaist.org Hypertrophic Obesity is Associated With Local and Systemic Inflammation and Insulin Resistance
  5. 5. Source: www.myhealthywaist.org Adapted from Virtue S & Vidal-Puig A Biochim Biophys Acta 2010:1801:338-49 Weight loss Increasing adipose tissue storage capacity Oxidation of lipids Storing of excess lipids in safe forms Increasing beta cell number or function Positive energy balance Failure in adipose tissue expansion Increased lipid flux to non- adipose organs Toxic lipid accummulation in non-adipose organs Beta cell compensation Local inflammation Insulin resistance Increased insulin demand Beta cell failure Hyperglycemia Steps Leading from Positive Energy Balance to Type 2 Diabetes
  6. 6. Source: www.myhealthywaist.org Hyperplasia Hypertrophy 1500 1000 500 0 Fatcellvolume(pl) Body fat mass (kg) A 0 20 40 60 80 100 1500 1000 500 0 Fatcellvolume(pl) Body fat mass (kg) B 120 0 50 100 150 200 150 50 0 Count Morphology value (pl) C -500 -300 -100 100 300 500 100 60 20 10 0 Frequency(%) D Men Women Nonobese Obese 50 40 30 Adapted from Arner E et al. Diabetes 2010;59:105-9 Adipose Morphology
  7. 7. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Clinical Findings in Women With Adipose Hyperplasia or Hypertrophy Adapted from Arner E et al. Diabetes 2010;59:105-9 Values are mean ± SD. Age was compared by unpaired t-test. Since it was slightly different between groups, the remaining values were compared by analysis of covariance with age as cofactor. Variables Hyperplasia (n=254) Hypertrophy (n=218) p value Age (years) 38 ± 10 40 ± 11 0.01 Waist (cm) 100 ± 22 105 ± 19 0.01 Waist-to-hip ratio 0.895 ± 0.085 0.924 ± 0.098 0.0005 Body mass index (kg/m2) 32.5 ± 9.4 33.1 ± 8.1 0.37 Glucose (mmol/l) 5.2 ± 1.4 5.4 ± 1.0 0.12 Insulin (mU/l) 10.1 ± 7.8 13.0 ± 7.7 <0.0001 HOMA index* 0.25 ± 0.33 0.42 ± 0.29 <0.0001 Cholesterol (mmol/l) 4.9 ± 1.0 5.1 ± 1.1 0.033 HDL cholesterol (mmol/l) 1.40 ± 0.39 1.28 ± 0.36 0.001 Triglycerides (mmol/l) 1.2 ± 0.8 1.5 ± 0.8 0.002 Fat cell volume (pl) 555 ± 224 825 ± 209 <0.0001 Fat cell number (x1010) 7.9 ± 2.8 5.3 ± 1.7 <0.0001 * Log 10 transformed
  8. 8. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org  Hypertrophic (enlarged adipose cells) obesity is associated with a dysregulated adipose tissue with reduced local and systemic insulin sensitivity irrespective of amount of body fat.  These include several markers of reduced cellular PPAR activation (reduced APM, GLUT4, FABP4, etc. and increased inflammation).  Ability to recruit new subcutaneous fat cells in (hyperplastic) obesity protects against the insulin-resistant obesity phenotype (metabolic syndrome). Insulin Resistance, Obesity and the Dysregulated Adipose Tissue APM: adipocyte-specific secretory protein FABP4: fatty acid binding protein 4 GLUT4: glucose transporter type 4 PPAR: peroxisome proliferator-activated receptor gamma
  9. 9. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Reduced IRS-1 in Adipocytes Copyright (1997) National Academy of Sciences, U.S.A. Proc Natl Acad Sci U S A 1997;94:4171-5 anti-IRS-1 anti-p85 anti-IR anti-syp C Type 2 diabetes Type 1 diabetes BLOT: IRS-1 BLOT: IRS-1 anti-IRS-1 (c-t) anti-IRS-1 (NH2-t) anti-p85 C Type 2 diabetes ← IRS-1 ← IRS-1 ← p85 anti-IR: insulin receptor antibody anti-IRS-1: insulin receptor substrate-1 antibody C: healthy control IRS-1: insulin receptor substrate-1
  10. 10. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org C Type 2 diabetes Type 1 diabetes BLOT: GLUT4 Reduced GLUT4 in Adipocytes C: healthy control GLUT4: glucose transporter type 4 From Smith U Unpublished data
  11. 11. Source: www.myhealthywaist.org Low IRS-1/ GLUT4 (n=20) Normal IRS-1/ GLUT4 (n=52) p value Cell size (µg/cell) 0.55 ± 0.03 0.42 ± 0.02 <0.001 Body mass index (kg/m2) 25.8 ± 0.6 24.6 ± 0.4 NS Waist-to-hip ratio 0.92 ± 0.02 0.84 ± 0.01 <0.001 Markers of impaired differentiation is ~4-times more frequent in first-degree relatives vs. nongenetic predisposition Question: Is impaired adipose cell differentiation with enlarged cells a consequence of genetic predisposition for type 2 diabetes and associated with insulin resistance? Adapted from Carvalho E et al. FASEB J 2001;15:1101-3 and Jansson PA et al. FASEB J 2003;17:1434-40 GLUT4: glucose transporter type 4 IRS-1: insulin receptor substrate-1 Enlarged Abdominal Adipose Cells in Individuals With Low IRS-1 Expression
  12. 12. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Lean individuals Genetic predisposition Type 2 diabetes Overweight or obesity Measure Yes (n=17) No (n=65) Yes (n=56) No (n=26) Age (years) 38 ± 2 33 ± 1 35 ± 1 32 ± 1 Waist circumference (cm) 82 ± 2(*) 79 ± 1 80 ± 1* 77 ± 1 BMI (kg/m2) 22.9 ± 0.4 22.4 ± 0.2 22.7 ± 0.2 22.2 ± 0.3 Body fat mass (kg) 19 ± 1 18 ± 1 18 ± 1 17 ± 1 Fat cell volume (pl) 511 ± 45** 400 ± 19 431 ± 23 407 ± 30 Delta value (pl) 64 ± 38** -37 ± 18 -15 ± 21 -18 ± 28 HOMA index 1.62 ± 0.24* 1.17 ± 0.08 1.26 ± 0.09 1.26 ± 0.16 HDL cholesterol (mmol/l) 1.39 ± 0.10* 1.62 ± 0.05 1.56 ± 0.07 1.60 ± 0.07 Apolipoprotein AI (mmol/l) 1.37 ± 0.07 1.48 ± 0.05 1.43 ± 0.05 1.51 ± 0.07 Apolipoprotein B (mmol/l) 0.94 ± 0.06(*) 0.82 ± 0.04 0.86 ± 0.04 0.84 ± 0.06 Apo B/apo AI 0.72 ± 0.07* 0.57 ± 0.03 0.63 ± 0.04 0.56 ± 0.04 Values are mean ± SE. Significances (by t-test) were only calculated between groups with heredity or not for type 2 diabetes and between groups with heredity or not for overweight or obesity. (*) 0.05<p<0.1, *p<0.05, **p=0.01 Comparison of Lean and Overweight Individuals With or Without a Genetic Predisposition for Type 2 Diabetes or Overweight/Obesity Adapted from Arner P et al. PLoS One 2011;6:e18284
  13. 13. Source: www.myhealthywaist.org Adipocyte Hypertrophy, Fatty Liver and Metabolic Risk Factors in South Asians: The Molecular Study of Health 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. Sharma Conclusions South 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
  14. 14. Source: www.myhealthywaist.org Adapted from Anand SS et al. PLoS One 2011;6:e22112 N=108 N=79 1.5 1.0 0.5 0.0 p=0.03 p=0.84 Age + sex + BMI Age + sex + BMI + adipocyte cell area HDL cholesterol (mmol/l) European South Asian 5.0 4.5 4.0 3.5 3.0 p=0.006 p=0.13 Fasting insulin-In (pmol/l) N=101 N=79 Age + sex + BMI Age + sex + BMI + adipocyte cell area N=108 N=79 9 8 7 6 5 p=0.002 p=0.15 Adiponectin (µg/ml) Age + sex + BMI Age + sex + BMI + adipocyte cell area Influence of Adipose Tissue Characteristics on Ethnic Differences in Adiponectin, Insulin and HDL cholesterol
  15. 15. Source: www.myhealthywaist.org Adapted from Anand SS et al. PLoS One 2011;6:e22112 European South Asian Liverfat(%) Age + sex + BMI Age + sex + BMI + adipocyte cell area N=95 N=74 Age + sex + BMI + adipocyte cell area + deep/superficial fat ratio N=55 p=0.005 p=0.04 p=0.30 14 12 10 8 6 4 2 0 Influence of Adipose Tissue Characteristics on Ethnic Differences in Liver Fat
  16. 16. Source: www.myhealthywaist.org Adapted from Anand SS et al. PLoS One 2011;6:e22112 Superficial subcutaneous adipose tissue Deep subcutaneous adipose tissue Excess energy Visceral depot Adipocyte hyperplasia Excess energy Visceral fat Adipocyte hypertrophy ↓ Adiponectin Fatty acid flux No liver fat Liver fat accumulation Abnormal response to chronic overnutrition (e.g. in South Asians vs. white Caucasians) No change in cardiometabolic factors Change in cardiometabolic factors: ↑ Insulin ↑ Glucose ↑ Triglycerides ↓ HDL cholesterol ↑ C-reactive protein ↑ Blood pressure Lower Capacity of South Asians to Store Fat in Subcutaneous Adipocytes Compared to White Caucasians Superficial subcutaneous adipose tissue Deep subcutaneous adipose tissue
  17. 17. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org  Genetic predisposition for type 2 diabetes is associated with a restricted adipogenesis and, thus, hypertrophic obesity even in the absence of obesity (body mass index).  Due to lack of precursor cells to undergo adipogenesis? (Diabetes 2009;58:1550-7)  Or inadequate signalling/activation of adipogenesis? Prime candidates:  BMP4 induces committment of precursor cells into the adipocyte lineage.  Canonical Wnt prevents PPAR activation and differentiation of preadipocytes. Summary BMP4: bone morphogenetic protein 4 PPAR: peroxisome proliferator-activated receptor gamma
  18. 18. Source: www.myhealthywaist.org Adapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24 Mesenchymal stem cells Myoblasts Osteoblasts Adipocytes Preadipocytes BMP4 Wnt + Wnt + Wnt - Wnt β-catenin + PPARγ C/EBPα C/EBPδ/β Adipocyte genes Preadipocyte genes Adipogenic stimuli BMP4: bone morphogenetic protein 4 C/EBPα: CCAAT/enhancer binding protein alpha C/EBPδ/β: CCAAT/enhancer ninding protein delta/beta PPAR: peroxisome proliferator-activated receptor gamma TNF-: tumor necrosis factor-alpha Canonical Wnt Signalling Regulates Mesenchymal Stem Cell Fate TNF- +
  19. 19. Source: www.myhealthywaist.org A) Nutritional deprivation AdipocytePreadipocyte Adipogenesis B) Overnutrition AdipocytePreadipocyte Adipogenesis Adipocyte hyperplasia C) Chronic overnutrition Hypertrophic adipocytes Preadipocyte Adipogenesis Ectopic lipid accumulation (liver and muscle) Adipose tissue inflammation Local Factors Regulates Adipogenesis Adapted from Christodoulides C et al. Trends Endocrinol Metab 2009;20:16-24
  20. 20. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org A Model for the Wnt Activation of the Beta-Catenin Signalling Pathway With Wnt Signal LRP Frizzled Axin Active dishevelled APC Inactive GSK-3β Stable β-catenin Unphosphorylated β-catenin migrates to nucleus and displaces groucho Groucho TranscriptionLEF-1/TCF Wnt From Smith U Unpublished data
  21. 21. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org Impaired Adipogenesis in Hypertrophic Obesity Adapted from Gustafson B & Smith U Diabetes 2012:61;1217-24 140 120 100 80 Cellsize(µm) Oil Red O (fold change) 0 1 2 3 4 60 40 5
  22. 22. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org  Is not due to lack of adipogenic precursor cells but to inappropriate inhibitory signalling.  BMP4 plays a role for precursor cell commitment and differentiation.  Wnt activation prevents the effect of BMP4 and is inappropriately activated in hypertrophic obesity. Hypertrophic Obesity BMP4: bone morphogenetic protein 4
  23. 23. Source: www.myhealthywaist.orgSource: www.myhealthywaist.org 1. Genetic predisposition for type 2 diabetes is associated with a restricted adipogenesis and hypertrophic obesity. 2. The restricted adipogenesis in hypertrophic obesity is not due to lack of precursor cells but to inadequate signalling/activation mainly involving inadequate suppression of canonical Wnt. Conclusions
  24. 24. Source: www.myhealthywaist.org

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