ABSTRACT
Despite consistent evidence that abnormalities of fatty acid delivery and storage underlie the metabolic defects of insulin resistance, physiological pathways by which fat is stored in adipose tissue and skeletal muscle are not clear. We used a combination of stable isotope labeling and arteriovenous difference measurements to elucidate pathways of postprandial fat deposition in adipose tissue and skeletal muscle in healthy humans. A test meal containing [U-(13)C]palmitate was combined with intravenous infusion of [(2)H(2)]palmitate to label plasma fatty acids and VLDL-triglyceride. Both dietary (chylomicron) and VLDL-triglyceride were cleared across adipose tissue and muscle, though with greater fractional extraction of the chylomicron-triglyceride. In adipose tissue there was significant uptake of plasma nonesterified fatty acids (NEFAs) in the postprandial but not the fasting state. However, this was minor in comparison with chylomicron-triglyceride fatty acids. We modeled the fate of fatty acids released by lipoprotein lipase (LPL). There was clear preferential uptake of these fatty acids compared with plasma NEFAs. In muscle, there was unexpected evidence for release of LPL-derived fatty acids into the plasma. With this integrative physiological approach, we have revealed hidden complexities in pathways of fatty acid uptake in adipose tissue and skeletal muscle.
Subject(s)
Adipose Tissue/physiology , Dietary Fats/metabolism , Fatty Acids, Nonesterified/pharmacokinetics , Muscle, Skeletal/physiology , Postprandial Period/physiology , Abdomen , Blood Flow Velocity/physiology , Blood Glucose/analysis , Deuterium , Fasting , Humans , Insulin/blood , Lipoproteins, HDL/blood , Male , Palmitic Acid/pharmacokinetics , Reference Values , Triglycerides/blood , Triglycerides/pharmacokineticsABSTRACT
CONTEXT: Low-grade inflammation in adipose tissue may contribute to insulin resistance in obesity. However, the roles of individual inflammatory mediators in adipose tissue are poorly understood. OBJECTIVES: The objective of this study was to determine which inflammation markers are most overexpressed at the gene level in adipose tissue in human obesity and how this relates to corresponding protein secretion. DESIGN: We examined gene expression profiles in 17 lean and 20 obese subjects. The secretory pattern of relevant corresponding proteins was examined in human s.c. adipose tissue or isolated fat cells in vitro and in vivo in several obese or lean cohorts. RESULTS: In ranking gene expression, defined pathways associated with obesity and immune and defense responses scored high. Among seven markedly overexpressed chemokines, only monocyte chemoattractant protein 1 (MCP1) was released from adipose tissue and isolated fat cells in vitro. In obesity, the secretion and expression of MCP1 in adipose tissue pieces were more than 6- and 2-fold increased, respectively, but there was no change in circulating MCP1 levels. There was no net release of MCP1, but there was a net release of leptin, in vivo from adipose tissue into the circulation. CONCLUSIONS: Obesity is associated with the increased expression of several chemokine genes in adipose tissue. However, only MCP1 is secreted into the extracellular space, where it primarily acts as a local factor, because little or no spillover into the circulation occurs. MCP1 influences the function of adipocytes, is a recruitment factor for macrophages, and may be a crucial link among chemokines between adipose tissue inflammation and insulin resistance.
Subject(s)
Adipose Tissue/physiopathology , Chemokine CCL2/physiology , Chemokines/physiology , Obesity/physiopathology , Adult , Body Mass Index , Chemokine CCL2/biosynthesis , Chemokines/biosynthesis , Female , Homeostasis/physiology , Humans , Immunity/physiology , Inflammation Mediators/physiology , Insulin Resistance , Male , Oligonucleotide Array Sequence Analysis , Proteins/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
OBJECTIVE: We aimed to determine differences in the postprandial contributions of different fatty acid sources to VLDL triglycerides (TGs) in healthy men and women with varying degrees of insulin resistance. RESEARCH DESIGN AND METHODS: Insulin-resistant (n = 11) and insulin-sensitive (n = 11) men and women (n = 6) were given an intravenous infusion of [(2)H(2)]palmitic acid to investigate systemic nonesterified fatty acid (NEFA) incorporation into VLDL TGs. Participants were also fed a mixed meal containing [U-(13)C]palmitic acid to investigate the contribution of dietary fatty acids to VLDL TG production. Blood samples were taken over the following 6 h. Separation of VLDL was performed by density gradient ultracentrifugation and immunoaffinity techniques specific to apolipoprotein B-100. RESULTS: Insulin-resistant and insulin-sensitive men had similar postprandial chylomicron and chylomicron remnant TG concentrations, but insulin-resistant men had higher postprandial VLDL TG concentrations (median [range]; area under the curve 485 micromol/l [123-992] vs. 287 micromol/l [162-510]; P < 0.05). At 360 min, most of the difference in VLDL TGs was accounted for by an additional contribution from splanchnic fat (means +/- SE; 331 +/- 76 micromol/l vs. 89 +/- 25 micromol/l; P < 0.01). The contribution of fatty acids from endogenous systemic NEFAs was similar across the groups, as were dietary fatty acids. There was no difference in the VLDL TG concentration or the contribution of different fatty acid sources between insulin-sensitive men and women. CONCLUSIONS: In the postprandial period, the only sources of fatty acids for VLDL TG production to differ in the insulin-resistant compared with the insulin-sensitive men are those derived from splanchnic sources.