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Fatty Acid Metabolism in Humans Michael Jensen, MD Division of Endocrinology and Metabolism Department of Internal Medicin...
Overview <ul><li>Adipose function in humans </li></ul><ul><li>Free fatty acids (FFA) and health </li></ul><ul><li>Regulati...
Fat and Lean Interactions Lean Body Mass Adipose tissue
Body Fat in Humans % body fat Lean men Lean women Obese men Obese women Adapted from Nielsen S et al. J Clin Invest 2004; ...
Regional Body Fat in Humans: Where Is It? SQ: subcutaneous  % of fat in region Lean men Lean women Adapted from Nielsen S ...
Regional Body Fat in Humans: Where Is It? SQ: subcutaneous % of fat in region Obese men Lower body obese women Upper body ...
Fatty Acid Metabolism in Humans <ul><li>Virtually all fatty acids originate from dietary triglyceride fatty acids. </li></...
Fatty Acid Metabolism in Humans Oxidation 100 gm TG fatty acids Chylomicron TG 100 gm FFA FFA: free fatty acids TG: trigly...
Adipose Physiology Insulin Triglycerides FFA: free fatty acids Adipocyte FFA Glycerol
Adipose Physiology Insulin Triglycerides FFA: free fatty acids Adipocyte    FFA    Glycerol
Adipose Physiology Growth hormone catecholamines Triglycerides FFA: free fatty acids Adipocyte FFA Glycerol
Adipose Physiology Triglycerides Growth hormone catecholamines FFA: free fatty acids Adipocyte    FFA    Glycerol
Energy Expenditure, Sex, and Free Fatty Acids (FFA) <ul><li>What drives the release of FFA in the postabsorptive state? </...
Energy Expenditure, Sex, and Free Fatty Acids (FFA) <ul><li>50 healthy research volunteers: </li></ul><ul><ul><ul><li>50% ...
Experimental Design <ul><li>Basal studies last 4 mornings of the study: </li></ul><ul><li>Palmitate flux = lipolysis (  m...
Resting Energy Expenditure vs.  Free Fatty Acid  Flux kcal/day Palmitate release (  mol/min) Women Men Adapted from Niels...
Intra-abdominal (Visceral) Fat Area vs. Residual Palmitate Flux 0 0 50 -50 300 Intra-abdominal fat area (cm 2 ) (umol/min)...
Summary <ul><li>Basal free fatty acid (FFA) release (lipolysis) is strongly related to resting energy expenditure. </li></...
Relationship Between Body Composition and Physiological Consequences <ul><li>Body fat distribution and free fatty acids (F...
Body Fat Distribution and Free Fatty Acids (FFA) Normal FFA  High FFA
Intra-abdominal (Visceral) Fat and Upper Body Obesity Subcutaneous fat  Intra-abdominal fat
Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance    FFA Insulin   resistance    Glucose  release ...
Body Fat Distribution and Free Fatty Acids (FFA) <ul><li>Upper body obesity is associated with adverse metabolic consequen...
Regional Adipose Tissue Model Intra-abdominal (visceral) fat Lower body subcutaneous fat Upper body subcutaneous fat
Splanchnic Contribution to Basal Upper Body Adipose Tissue Free Fatty Acid Release  mol/min * Adapted from Martin ML and ...
Regional Free Fatty Acid Release During Meal Ingestion *  mol/min Nonsplanchnic upper body Leg Splanchnic Nonsplanchnic u...
Regional Free Fatty Acid Release in Obese Nondiabetics and Obese Type 2 Diabetics Adapted from Basu A et al. Am J Physiol ...
Hepatic Free Fatty Acid (FFA) Delivery Intra-abdominal (visceral) fat area (cm 2 ) % Hepatic FFA delivery  from intra-abdo...
Summary <ul><li>Upper body subcutaneous fat accounted for the majority of systemic free fatty acid (FFA) release. </li></u...
Summary <ul><li>A greater portion of free fatty acid (FFA) appearance derives from leg and splanchnic adipose tissue in ob...
Conclusions <ul><li>In both men and women, greater amounts of intra-abdominal (visceral) fat result in a greater proportio...
Free Fatty Acids (FFA) and Pancreas Insulin resistance    FFA <ul><li>Long-term damage to  </li></ul><ul><li>beta cells <...
Free Fatty Acids (FFA) and Dyslipidemia    VLDL-TG    HDL cholesterol    Apo B100 synthesis and secretion Insulin resis...
Free Fatty Acids (FFA) and Glucose Production Insulin resistance    FFA    Glucose release Adipose tissue Liver
Free Fatty Acids (FFA) and Muscle Skeletal muscle cells Intra-muscular TG Insulin resistance    Glucose uptake Insulin re...
Free Fatty Acids (FFA) and Hypertension    Relaxation – decreased nitric oxide generation    Constriction – greater resp...
Summary <ul><li>Upper body obesity is associated with high free fatty acids (FFA) due to excess release from upper body su...
Conclusion <ul><li>Therapies that correct abnormal adipose tissue free fatty acid release may improve the metabolic abnorm...
Adipose Tissue as Endocrine Cells Angiotensinogen Resistin Retinol binding protein-4 Visfatin Interleukin-6 Tumor necrosis...
Conclusions <ul><li>Fat is a dynamic and varied tissue. </li></ul><ul><li>Regional differences in adipose biology affect h...
<ul><li>www.cardiometabolic-risk.org </li></ul>
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Fatty acid metabolism in humans

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By Michael Jensen, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA.

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  • An incompletely understood issue is how adipose tissue and lean tissue interact to produce the adverse metabolic consequences of obesity.
  • This shows the average percent body fat in normal weight men and women, as well as in men and women with a body mass index between 30 – 35 kg/m 2 .
  • This shows the average percent body fat in normal weight men and women, as well as in men and women with a body mass index between 30 – 35 kg/m 2 .
  • This shows the average percent body fat in normal weight men and women, as well as in men and women with a body mass index between 30 – 35 kg/m 2 .
  • This depicts the fate of fatty acids in the average diet of weight stable adults in most Western countries.
  • Under resting, postabsorptive conditions, free fatty acids and glycerol are released from adipocytes. With meal ingestion, insulin secretion increases substantially.
  • Under resting, postabsorptive conditions, free fatty acids and glycerol are released from adipocytes. With meal ingestion, insulin secretion increases substantially.
  • Under resting, postabsorptive conditions, free fatty acids and glycerol are released from adipocytes. With meal ingestion, insulin secretion increases substantially.
  • Under resting, postabsorptive conditions, free fatty acids and glycerol are released from adipocytes. With meal ingestion, insulin secretion increases substantially.
  • This shows the relationship between basal metabolic rate (kcal/day) and palmitate (one of the major free fatty acids) release in men and women. Women have 40% greater free fatty acid release than men at the same metabolic rate, the same fat oxidation rates, and the same FFA concentrations.
  • This shows the relationship between intra-abdominal (visceral) fat area as measured by single slice computed tomography and the residual variance in palmitate release relative to REE in men and women. Visceral fat correlated with the residual variance in free fatty release release in men. Not shown: plasma epinephrine concentrations also were correlated with the residual variance in FFA release.
  • Women with lower body obesity tend to have normal free fatty acid metabolism whereas women with upper body obesity have high free fatty acid concentrations and release under most circumstances.
  • Is visceral fat the source of excess free fatty acids in upper body obesity?
  • Artificial elevation of free fatty acids in lean humans can cause muscle insulin resistance, endothelial dysregulation, abnormal insulin secretion, and impair insulin’s ability to suppress hepatic glucose release. Thus, the high free fatty acids in upper body obesity may play an important role in the adverse metabolic consequences of obesity.
  • We measured regional free fatty acid uptake and release using isotope dilution and regional blood flow techniques in persons with catheters placed in the femoral artery, femoral vein, and hepatic veins to collect blood samples.
  • The excess free fatty acid release in upper body obese women compared with lower body obese women originates from upper body subcutaneous, not visceral, fat under postabsorptive conditions.
  • Under postprandial conditions, the excess free fatty acid release in upper body obesity compared with lower body obesity also originates from upper body subcutaneous fat, not visceral or leg fat.
  • Under insulin-suppressed conditions, the relative contribution of visceral (splanchnic) free fatty acid release is not different in viscerally obese type 2 diabetics compared with non-diabetic obese control subjects.
  • A novel model of portal free fatty acid delivery to liver was used to determine the relationship between visceral fat and the proportion of hepatic free fatty acid delivery from visceral lipolysis. Although persons with greater amounts of visceral fat do have slightly greater portions of hepatic free fatty acid delivery from omental and mesenteric adipose tissue free fatty acid release, the majority of hepatic free fatty acid delivery was found to come from the systemic circulation.
  • The higher free fatty acid concentrations in upper body obesity that can affect pancreatic function are from systemic FFA, and thus largely originate from upper body subcutaneous fat.
  • The higher free fatty acid concentrations in upper body obesity that can affect pancreatic function are from systemic FFA, and thus largely originate from upper body subcutaneous fat.
  • The higher free fatty acid concentrations in upper body obesity that can affect pancreatic function are from systemic FFA, and thus largely originate from upper body subcutaneous fat.
  • The higher free fatty acid concentrations in upper body obesity that can affect pancreatic function are from systemic FFA, and thus largely originate from upper body subcutaneous fat.
  • The higher free fatty acid concentrations in upper body obesity that can affect pancreatic function are from systemic FFA, and thus largely originate from upper body subcutaneous fat.
  • In addition to the free fatty acid release functions of adipose tissue, it has been shown to release a large number of “adipokines”. These range from typical inflammatory cytokines (tumor necrosis factor- α and interleukin-6) to insulin sensitizing molecules (adiponectin and visfatin) and molecules thought to induce insulin resistance (retinol binding protein-4).
  • Transcript of "Fatty acid metabolism in humans"

    1. 1. 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. 2. Overview <ul><li>Adipose function in humans </li></ul><ul><li>Free fatty acids (FFA) and health </li></ul><ul><li>Regulation of FFA metabolism </li></ul><ul><li>FFA in different types of obesity </li></ul>
    3. 3. Fat and Lean Interactions Lean Body Mass Adipose tissue
    4. 4. 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. 5. Regional Body Fat in Humans: Where Is It? SQ: subcutaneous % of fat in region Lean men Lean women Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8
    6. 6. Regional Body Fat in Humans: Where Is It? SQ: subcutaneous % 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. 7. Fatty Acid Metabolism in Humans <ul><li>Virtually all fatty acids originate from dietary triglyceride fatty acids. </li></ul><ul><li>Long-term storage site is adipose tissue. </li></ul><ul><li>Regulated release of fatty acids as free fatty acids provides the majority of lipid fuel for postabsorptive adults. </li></ul>
    8. 8. Fatty Acid Metabolism in Humans Oxidation 100 gm TG fatty acids Chylomicron TG 100 gm FFA FFA: free fatty acids TG: triglycerides Direct Oxidation CO 2 + H 2 O (20-70 gm) Adipose tissue (30-80 gm)
    9. 9. Adipose Physiology Insulin Triglycerides FFA: free fatty acids Adipocyte FFA Glycerol
    10. 10. Adipose Physiology Insulin Triglycerides FFA: free fatty acids Adipocyte  FFA  Glycerol
    11. 11. Adipose Physiology Growth hormone catecholamines Triglycerides FFA: free fatty acids Adipocyte FFA Glycerol
    12. 12. Adipose Physiology Triglycerides Growth hormone catecholamines FFA: free fatty acids Adipocyte  FFA  Glycerol
    13. 13. Energy Expenditure, Sex, and Free Fatty Acids (FFA) <ul><li>What drives the release of FFA in the postabsorptive state? </li></ul><ul><li>What is “normal” FFA release? </li></ul><ul><li>How does FFA release differ in men and women, lean and obese? </li></ul><ul><li>Does body fat distribution relate to basal lipolysis? </li></ul><ul><li>Do circulating hormone levels relate to basal lipolysis? </li></ul>
    14. 14. Energy Expenditure, Sex, and Free Fatty Acids (FFA) <ul><li>50 healthy research volunteers: </li></ul><ul><ul><ul><li>50% women (all premenopausal) </li></ul></ul></ul><ul><ul><ul><li>50% obese </li></ul></ul></ul><ul><li>Body composition: </li></ul><ul><ul><ul><li>DEXA (fat and fat-free mass) </li></ul></ul></ul><ul><ul><ul><li>CT abdomen for visceral and subcutaneous fat </li></ul></ul></ul><ul><ul><ul><li>Fat cell size (abdomen & gluteal) </li></ul></ul></ul><ul><li>Isoenergetic diet in GCRC x 2 weeks </li></ul>DEXA: dual energy x-ray absorptiometry CT: computed tomography
    15. 15. Experimental Design <ul><li>Basal studies last 4 mornings of the study: </li></ul><ul><li>Palmitate flux = lipolysis (  mol/min - [U 13 C]palmitate) </li></ul><ul><li>Resting energy expenditure (indirect calorimetry) </li></ul>
    16. 16. Resting Energy Expenditure vs. Free Fatty Acid Flux kcal/day Palmitate release (  mol/min) Women Men Adapted from Nielsen S et al. J Clin Invest 2003; 111: 981-8
    17. 17. 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 0 0 50 -50 300 R esidual palmit a t e r elease Intra-abdominal fat area (cm 2 ) (  mol/min) Residual palmitate release Adapted from Nielsen S et al. J Clin Invest 2003; 111: 981-8 Men Women
    18. 18. Summary <ul><li>Basal free fatty acid (FFA) release (lipolysis) is strongly related to resting energy expenditure. </li></ul><ul><li>Women have higher FFA release rates than men at comparable resting energy expenditure and comparable FFA concentrations . </li></ul><ul><li>This sex-based difference can only be due to increased non-oxidative FFA clearance in women. </li></ul><ul><li>Basal FFA release is partially modulated by body fat and catecholamine availability. </li></ul>
    19. 19. Relationship Between Body Composition and Physiological Consequences <ul><li>Body fat distribution and free fatty acids (FFA) </li></ul><ul><li>Adipose tissue FFA release </li></ul><ul><li>Effects of excess FFA on health </li></ul>
    20. 20. Body Fat Distribution and Free Fatty Acids (FFA) Normal FFA High FFA
    21. 21. Intra-abdominal (Visceral) Fat and Upper Body Obesity Subcutaneous fat Intra-abdominal fat
    22. 22. Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance  FFA Insulin resistance  Glucose release  Constriction  Relaxation  Insulin secretion Insulin resistance Muscle Vasculature Liver Pancreas Upper body / Intra-abdominal obesity
    23. 23. Body Fat Distribution and Free Fatty Acids (FFA) <ul><li>Upper body obesity is associated with adverse metabolic consequences. </li></ul><ul><li>Upper body obesity is associated with high basal and postprandial FFA. </li></ul><ul><li>Intra-abdominal (visceral) fat most strongly correlated with metabolic abnormalities. </li></ul><ul><li>Do the excess FFAs come from intra-abdominal fat? </li></ul>
    24. 24. Regional Adipose Tissue Model Intra-abdominal (visceral) fat Lower body subcutaneous fat Upper body subcutaneous fat
    25. 25. Splanchnic Contribution to Basal Upper Body Adipose Tissue Free Fatty Acid Release  mol/min * 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. 26. Regional Free Fatty Acid Release During Meal Ingestion *  mol/min Nonsplanchnic upper body Leg Splanchnic Nonsplanchnic upper body Leg Splanchnic * p<0.05 vs. basal values Adapted from Guo Z et al. Diabetes 1999; 48: 1586-93 * * * Upper body obese Lower body obese
    27. 27. 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. 28. Hepatic Free Fatty Acid (FFA) Delivery Intra-abdominal (visceral) fat area (cm 2 ) % Hepatic FFA delivery from intra-abdominal fat Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8 Women Men
    29. 29. Summary <ul><li>Upper body subcutaneous fat accounted for the majority of systemic free fatty acid (FFA) release. </li></ul><ul><li>Intra-abdominal (visceral) fat mass correlated with but was not the source of most systemic FFA release. </li></ul><ul><li>Intra-abdominal fat mass predicts greater delivery of FFA to the liver from intra-abdominal lipolysis. </li></ul>
    30. 30. Summary <ul><li>A greater portion of free fatty acid (FFA) appearance derives from leg and splanchnic adipose tissue in obese than lean men and women. </li></ul><ul><li>Nevertheless, the majority of systemic FFAs originate from upper body subcutaneous fat in obese men and women. </li></ul><ul><li>Intra-abdominal (visceral) fat correlates positively with the proportion of hepatic FFA delivery from intra-abdominal fat in both men and women. </li></ul>
    31. 31. Conclusions <ul><li>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. </li></ul><ul><li>This implies that arterial FFA concentrations will underestimate hepatic FFA delivery systematically and progressively with greater degrees of intra-abdominal adiposity. </li></ul>
    32. 32. Free Fatty Acids (FFA) and Pancreas Insulin resistance  FFA <ul><li>Long-term damage to </li></ul><ul><li>beta cells </li></ul><ul><li>Decreased insulin </li></ul><ul><li>secretion </li></ul>Short-term stimulation of insulin secretion Pancreas Adipose tissue
    33. 33. Free Fatty Acids (FFA) and Dyslipidemia  VLDL-TG  HDL cholesterol  Apo B100 synthesis and secretion Insulin resistance  FFA TG: triglycerides Liver Adipose tissue
    34. 34. Free Fatty Acids (FFA) and Glucose Production Insulin resistance  FFA  Glucose release Adipose tissue Liver
    35. 35. Free Fatty Acids (FFA) and Muscle Skeletal muscle cells Intra-muscular TG Insulin resistance  Glucose uptake Insulin resistance FFA TG: triglycerides Muscle Adipose tissue
    36. 36. Free Fatty Acids (FFA) and Hypertension  Relaxation – decreased nitric oxide generation  Constriction – greater response to alpha-adrenergic stimuli Insulin resistance  FFA Vasculature Adipose tissue
    37. 37. Summary <ul><li>Upper body obesity is associated with high free fatty acids (FFA) due to excess release from upper body subcutaneous fat. </li></ul><ul><li>High FFA can result in: </li></ul><ul><ul><li>insulin resistance in muscle and liver </li></ul></ul><ul><ul><li> VLDL TG </li></ul></ul><ul><ul><li> insulin secretion (?diabetes) </li></ul></ul><ul><ul><li>vascular abnormalities </li></ul></ul>
    38. 38. Conclusion <ul><li>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. </li></ul>
    39. 39. Adipose Tissue as Endocrine Cells Angiotensinogen Resistin Retinol binding protein-4 Visfatin Interleukin-6 Tumor necrosis factor-  Adiponectin Leptin
    40. 40. Conclusions <ul><li>Fat is a dynamic and varied tissue. </li></ul><ul><li>Regional differences in adipose biology affect health. </li></ul><ul><li>The causes of differences in body fat distribution are unknown. </li></ul><ul><li>The relative contributions of high free fatty acids and adipokines to adverse health is unknown. </li></ul>
    41. 41. <ul><li>www.cardiometabolic-risk.org </li></ul>
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