Fatty Acid Metabolism in Humans r Michael Jensen

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Intra-abdominal (Visceral) Fat Area vs. Residual Palmitate Flux Men Women 50 50 Residual palmitate release ( mol/min) R esidual palmit 0 0 0 300 (umol/min) r=0. 45 p<0. 05 -50 a te release -50 Intra-abdominal fat area (cm 2) Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org Intra-abdominal fat area (cm 2) Adapted from Nielsen S et al. J Clin Invest 2003; 111: 981 -8

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

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

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

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

Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance Muscle Upper body / Intra-abdominal obesity Insulin resistance Insulin resistan ce Constriction Relaxation FFA Liver Glucose release Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org Vasculature Pancreas Insulin secretion

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

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

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

mol/min Regional Free Fatty Acid Release During Meal Ingestion * * * Nonsplanchnic upper body Splanchnic Leg Upper body obese * Nonsplanchnic upper body Splanchnic Leg Lower body obese * p<0. 05 vs. basal values Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org Adapted from Guo Z et al. Diabetes 1999; 48: 1586 -93

Percent of total Regional Free Fatty Acid Release in Obese Nondiabetics and Obese Type 2 Diabetics Nondiabetic Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org Diabetic Adapted from Basu A et al. Am J Physiol 2001; 280: E 1000 -6

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

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

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

Conclusions r 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 intraabdominal adipose tissue lipolysis in the overnight postabsorptive state. r This implies that arterial FFA concentrations will underestimate hepatic FFA delivery systematically and progressively with greater degrees of intra-abdominal adiposity. Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org

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

Free Fatty Acids (FFA) and Dyslipidemia Insulin resistance FFA Liver Adipose tissue Apo B 100 synthesis and secretion VLDL-TG TG: triglycerides Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org HDL cholesterol

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

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

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

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

Conclusion r 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. Source: International Chair on Cardiometabolic Risk www. cardiometabolic-risk. org

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

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

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