Splanchnic Spillover of Extracellular Lipase–Generated Fatty Acids in Overweight and Obese Humans

Abstract

OBJECTIVE-Triglyceride-rich lipoproteins, primarily chylomicrons, can contribute to plasma free fatty acid (FFA) concentrations via spillover of fatty acids during intravascular hydrolysis into the venous effluent of some tissues. The present study was undertaken to determine whether spillover occurs in the splanchnic bed of humans.RESEARCH DESIGN AND METHODS-Arterial and hepatic venous blood was sampled in postabsorptive (n ϭ 6; study A) and postprandial (n ϭ 5; study B) obese humans during infusion of carbon-labeled ( 14 C or 13 C) oleate and 3 H triolein, the latter incorporated into a lipid emulsion as a surrogate for chylomicrons. Spillover was determined by measuring production of 3 H oleate.RESULTS-Splanchnic spillover was higher than nonsplanchnic systemic spillover in both study A (60 Ϯ 7 vs. 24 Ϯ 6%; P Ͻ 0.01) and study B (54 Ϯ 3 vs. 16 Ϯ 5%; P Ͻ 0.005). Because portal vein sampling is not feasible in humans, assumptions regarding actual spillover in nonhepatic splanchnic tissues were required for the spillover calculation. A mathematical model was developed and demonstrated that nonhepatic splanchnic spillover rates in study A and study B of 69 and 80%, respectively, provided the best fit with the data. There was preferential splanchnic uptake of triglyceride fatty acids compared with FFAs in study B (fractional extraction 61 Ϯ 3 vs. 33 Ϯ 2%; P Ͻ 0.005).CONCLUSIONS-These data confirm previous studies indicating that the transport of FFAs and triglyceride fatty acids are partitioned in tissues and indicate that splanchnic spillover from triglyceride-rich lipoproteins may be a significant source of both portal venous and systemic FFAs. Diabetes 56:2878-2884, 2007 E pidemiologic data linking visceral adipose tissue to an increased risk of cardiovascular disease and type 2 diabetes have stimulated considerable study and conjecture as to the mechanism of this relationship. Bjorntorp (1) proposed that increased delivery of free fatty acids (FFAs) to the liver via the portal vein may be the main culprit. Increased portal venous FFAs are thought to lead to increased VLDL triglyceride production (2), to hepatic insulin resistance (3), and to impaired insulin extraction by the liver with subsequent hyperinsulinemia (4).Visceral fat is a known source of portal venous FFAs but only a minor source of peripheral FFAs (5). Upper body fat is known to be metabolically different from lower body fat, characterized by increased lipolysis. Whether visceral fat is hyperlipolytic has been questioned (6). Although it is generally thought that the majority of FFAs are derived from the action of intracellular lipases on adipose tissue triglycerides, intravascular lipases such as lipoprotein lipase (LPL) can hydrolyze triglycerides in circulating triglyceride-rich lipoproteins and, thus, can be an additional source. It has previously been demonstrated that some fatty acids produced by intravascular lipolysis are released, or "spilled over," into the plasma FFA pool; this phenomenon has been documented in human adipose tissue, f...

Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography

“…This finding is consistent with the known preferential liver uptake of intravenously administered fatty acid tracers in animals (10). It is also consistent with the higher NEFA spillover rate from circulating TG in the splanchnic vs. systemic circulation in humans (25) and with hepatic uptake of chylomicron remnants (13). The relatively high cardiac dietary fatty acid uptake that we observed is also consistent with significant myocardial uptake of circulating TG in humans (26).…”

“…To our knowledge, this is the first study to report a method that can quantify dietary fatty acid absorption and assembly into chylomicron, their delivery into the thoracic duct, and their simultaneous distribution and uptake into all tissues and organs in humans. Although it has been possible in some instances to use an arteriovenous gradient even across the heart or liver circulation or visceral adipose tissue biopsies during abdominal surgery to determine circulating TG and/or NEFA metabolism in these internal organs in humans (16,21,25,26), these studies are very invasive and difficult to perform, making assessment of organ-specific metabolism of dietary fatty acids impossible in most situations. In addition, it has previously been impossible to simultaneously measure partition of dietary fatty acids in all internal organs in humans, a major advantage of the novel method described herein.…”

Effect of Insulin Infusion on Spillover of Meal-Derived Fatty Acids

“…In a previous study in overweight and obese subjects, we found that more than half of systemic spillover occurs in the splanchnic bed (8); studies in dogs showed a strong relationship between fractional spillover and intracellular lipolysis in visceral fat (10). In the present study, insulin was infused during continuous meal absorption to induce suppression of adipose tissue lipolysis additional to that achieved by the meal.…”

“…Fractional spillover in various studies has been estimated to be about 30 -40% of LPLgenerated fatty acids (7)(8)(9) and, depending on dietary fat intake, could account for 25% or more of total FFA flux (7). We previously reported that the majority of spillover in overweight and obese humans occurs in the splanchnic bed, probably in visceral adipose tissue (8,10). Spillover correlates strongly with release of FFAs by intracellular lipases in visceral fat, suggesting that it is regulated by intracellular lipolysis (10).…”

“…Although it is generally thought that the main source of FFAs is the adipocyte triglyceride depot, regulated by intracellular lipases (6), the action of lipoprotein lipase (LPL) on chylomicrons is an additional source of plasma FFAs, released into the circulation by a spillover mechanism (7). Fractional spillover in various studies has been estimated to be about 30 -40% of LPLgenerated fatty acids (7)(8)(9) and, depending on dietary fat intake, could account for 25% or more of total FFA flux (7). We previously reported that the majority of spillover in overweight and obese humans occurs in the splanchnic bed, probably in visceral adipose tissue (8,10).…”