1. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Fatty Acid Metabolism in Humans Michael Jensen, MD Division of Endocrinology and Metabolism Department of Internal Medicine Mayo Clinic and Foundation, Rochester, MN, USA

2. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Overview  Adipose function in humans  Free fatty acids (FFA) and health  Regulation of FFA metabolism  FFA in different types of obesity

3. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Fat and Lean Interactions Lean Body Mass Adipose tissue

4. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Body Fat in Humans % body fat Lean men Lean women Obese men Obese women Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8

5. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org SQ: subcutaneous Regional Body Fat in Humans: Where Is It? % of fat in region Lean men Lean women Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8

6. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org SQ: subcutaneous Regional Body Fat in Humans: Where Is It? % of fat in region Obese men Lower body obese women Upper body obese women Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8

7. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Fatty Acid Metabolism in Humans  Virtually all fatty acids originate from dietary triglyceride fatty acids.  Long-term storage site is adipose tissue.  Regulated release of fatty acids as free fatty acids provides the majority of lipid fuel for postabsorptive adults.

8. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Fatty Acid Metabolism in Humans Oxidation 100 gm TG fatty acids Chylomicron TG 100 gm FFA Direct Oxidation CO 2 + H 2 O (20-70 gm) Adipose tissue (30-80 gm) FFA: free fatty acids TG: triglycerides

9. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Insulin Adipocyte Triglycerides FFA Glycerol FFA: free fatty acids

10. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Insulin Adipocyte Triglycerides  FFA  Glycerol FFA: free fatty acids

11. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Growth hormone catecholamines Adipocyte Triglycerides FFA Glycerol FFA: free fatty acids

12. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Adipocyte Triglycerides  FFA  Glycerol Growth hormone catecholamines FFA: free fatty acids

13. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Energy Expenditure, Sex, and Free Fatty Acids (FFA)  What drives the release of FFA in the postabsorptive state?  What is “normal” FFA release?  How does FFA release differ in men and women, lean and obese?  Does body fat distribution relate to basal lipolysis?  Do circulating hormone levels relate to basal lipolysis?

14. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Energy Expenditure, Sex, and Free Fatty Acids (FFA)  50 healthy research volunteers: 50% women (all premenopausal) 50% obese  Body composition: DEXA (fat and fat-free mass) CT abdomen for visceral and subcutaneous fat Fat cell size (abdomen & gluteal)  Isoenergetic diet in GCRC x 2 weeks DEXA: dual energy x-ray absorptiometry CT: computed tomography

15. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Experimental Design  Basal studies last 4 mornings of the study:  Palmitate flux = lipolysis (  mol/min - [U 13 C]palmitate)  Resting energy expenditure (indirect calorimetry)

16. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org kcal/day Palmitate release (  mol/min) Resting Energy Expenditure vs. Free Fatty Acid Flux Women Men Adapted from Nielsen S et al. J Clin Invest 2003; 111: 981-8

17. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat Area vs. Residual Palmitate Flux 0 0 50 -50 300 Intra-abdominal fat area (cm 2 ) (umol/min) r=0.45 p<0.05 Men 0 0 50 -50 300 R esidual palmit a t e r elease Women Intra-abdominal fat area (cm 2 ) (  mol/min) Residual palmitate release Adapted from Nielsen S et al. J Clin Invest 2003; 111: 981-8

18. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Summary  Basal free fatty acid (FFA) release (lipolysis) is strongly related to resting energy expenditure.  Women have higher FFA release rates than men at comparable resting energy expenditure and comparable FFA concentrations.  This sex-based difference can only be due to increased non-oxidative FFA clearance in women.  Basal FFA release is partially modulated by body fat and catecholamine availability.

19. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Relationship Between Body Composition and Physiological Consequences  Body fat distribution and free fatty acids (FFA)  Adipose tissue FFA release  Effects of excess FFA on health

20. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Body Fat Distribution and Free Fatty Acids (FFA) Normal FFAHigh FFA

21. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat and Upper Body Obesity Subcutaneous fat Intra-abdominal fat

22. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org  FFA Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance Insulin resistance  Glucose release  Constriction  Relaxation  Insulin secretion MuscleVasculature LiverPancreas Upper body / Intra-abdominal obesity Insulin resistance

23. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Body Fat Distribution and Free Fatty Acids (FFA)  Upper body obesity is associated with adverse metabolic consequences.  Upper body obesity is associated with high basal and postprandial FFA.  Intra-abdominal (visceral) fat most strongly correlated with metabolic abnormalities.  Do the excess FFAs come from intra- abdominal fat?

24. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Regional Adipose Tissue Model Intra-abdominal (visceral) fat Lower body subcutaneous fat Upper body subcutaneous fat

25. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org  mol/min Splanchnic Contribution to Basal Upper Body Adipose Tissue Free Fatty Acid Release * Adapted from Martin ML and Jensen M. J Clin Invest 1991; 88: 609-13 Lean women Lower body obese women Upper body obese women

26. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Regional Free Fatty Acid Release During Meal Ingestion Upper body obeseLower body obese *  mol/min Nonsplanchnic upper body LegSplanchnic Nonsplanchnic upper body LegSplanchnic * p<0.05 vs. basal values Adapted from Guo Z et al. Diabetes 1999; 48: 1586-93 * * *

27. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Regional Free Fatty Acid Release in Obese Nondiabetics and Obese Type 2 Diabetics Adapted from Basu A et al. Am J Physiol 2001; 280: E1000-6 Percent of total Nondiabetic Diabetic

28. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (visceral) fat area (cm 2 ) % Hepatic FFA delivery from intra-abdominal fat Hepatic Free Fatty Acid (FFA) Delivery Women Men Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8

29. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Summary  Upper body subcutaneous fat accounted for the majority of systemic free fatty acid (FFA) release.  Intra-abdominal (visceral) fat mass correlated with but was not the source of most systemic FFA release.  Intra-abdominal fat mass predicts greater delivery of FFA to the liver from intra- abdominal lipolysis.

30. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Summary  A greater portion of free fatty acid (FFA) appearance derives from leg and splanchnic adipose tissue in obese than lean men and women.  Nevertheless, the majority of systemic FFAs originate from upper body subcutaneous fat in obese men and women.  Intra-abdominal (visceral) fat correlates positively with the proportion of hepatic FFA delivery from intra-abdominal fat in both men and women.

31. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Conclusions  In both men and women, greater amounts of intra-abdominal (visceral) fat result in a greater proportion of hepatic free fatty acid (FFA) delivery originating from intra- abdominal adipose tissue lipolysis in the overnight postabsorptive state.  This implies that arterial FFA concentrations will underestimate hepatic FFA delivery systematically and progressively with greater degrees of intra-abdominal adiposity.

32. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Free Fatty Acids (FFA) and Pancreas Insulin resistance  FFA Long-term damage to beta cells Decreased insulin secretion Short-term stimulation of insulin secretion Pancreas Adipose tissue

33. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Free Fatty Acids (FFA) and Dyslipidemia Liver  VLDL-TG  HDL cholesterol  Apo B100 synthesis and secretion Insulin resistance  FFA Adipose tissue TG: triglycerides

34. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Free Fatty Acids (FFA) and Glucose Production Insulin resistance  FFA Adipose tissue Liver  Glucose release

35. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Skeletal muscle cells Free Fatty Acids (FFA) and Muscle Intra- muscular TG Insulin resistance  Glucose uptake Muscle Insulin resistance FFA Adipose tissue TG: triglycerides

36. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Free Fatty Acids (FFA) and Hypertension  Relaxation – decreased nitric oxide generation Vasculature  Constriction – greater response to alpha- adrenergic stimuli Insulin resistance  FFA Adipose tissue

37. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Summary  Upper body obesity is associated with high free fatty acids (FFA) due to excess release from upper body subcutaneous fat.  High FFA can result in: –insulin resistance in muscle and liver –  VLDL TG –  insulin secretion (?diabetes) –vascular abnormalities

38. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Conclusion  Therapies that correct abnormal adipose tissue free fatty acid release may improve the metabolic abnormalities seen in upper body obesity even if weight loss is not successful.

39. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Tissue as Endocrine Cells Angiotensinogen Resistin Retinol binding protein-4 Visfatin Interleukin-6 Tumor necrosis factor-  Adiponectin Leptin

40. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Conclusions  Fat is a dynamic and varied tissue.  Regional differences in adipose biology affect health.  The causes of differences in body fat distribution are unknown.  The relative contributions of high free fatty acids and adipokines to adverse health is unknown.

41. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org  www.cardiometabolic-risk.org