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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
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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
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Fat and Lean Interactions Lean Body Mass Adipose tissue
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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
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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
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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
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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.
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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
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Insulin Adipocyte Triglycerides FFA Glycerol FFA: free fatty acids
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Insulin Adipocyte Triglycerides FFA Glycerol FFA: free fatty acids
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Growth hormone catecholamines Adipocyte Triglycerides FFA Glycerol FFA: free fatty acids
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Adipose Physiology Adipocyte Triglycerides FFA Glycerol Growth hormone catecholamines FFA: free fatty acids
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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?
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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
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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)
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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
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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
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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.
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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
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Body Fat Distribution and Free Fatty Acids (FFA) Normal FFAHigh FFA
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat and Upper Body Obesity Subcutaneous fat Intra-abdominal fat
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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
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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?
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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
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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
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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 * * *
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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
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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
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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.
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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.
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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.
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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
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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
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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
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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
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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
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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
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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.
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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
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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.
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Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org www.cardiometabolic-risk.org
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