Samyah Shadid

Direct Free Fatty Acid Uptake Into Human Adipocytes In Vivo: Relation to Body Fat Distribution

We sought to assess whether direct uptake of circulating free fatty acids (FFAs) by adipocytes occurs in vivo in overnight postabsorptive humans and, if so, whether there are regional differences in uptake between lean and obese women and men. We used bolus injections of radiolabeled FFA tracers followed by carefully timed adipose tissue biopsies. First, we validated a method to measure direct adipocyte FFA uptake and then quantitated this process using the modified methods in normal-weight postabsorptive men and women. We then used a continuous infusion of radiolabeled FFA to measure direct and indirect (VLDL) regional adipose tissue uptake in obese men and women. Direct FFA uptake was greater in women than men: 8.2 ± 0.6 vs. 4.0 ± 0.5% (P < 0.0001) of FFAs were taken up by subcutaneous adipose tissue, respectively. Abdominal subcutaneous fat took up FFAs more avidly than femoral fat in men, but this did not occur in women. Similar sex and regional difference were found to occur in obese women and men. Gene expression of fatty acid transporters was greater in abdominal than femoral fat in men (P < 0.05) but not in women (P = 0.80). We observed sex- and site-specific recycling of circulating FFAs into subcutaneous fat. This is a novel FFA disposal pathway that may also play a role in the development or maintenance of body fat distribution. Regional variations in facilitated fatty acid transport may contribute to this process.

Relationship between plasma free fatty acid, intramyocellular triglycerides and long-chain acylcarnitines in resting humans

We hypothesized that plasma non‐esterified fatty acids (NEFA) are trafficked directly to intramyocellular long‐chain acylcarnitines (imLCAC) rather than transiting intramyocellular triglycerides (imTG) on the way to resting muscle fatty acid oxidation. Overnight fasted adults (n= 61) received intravenous infusions of [U‐13C]palmitate (0400–0830 h) and [U‐13C]oleate (0800–1400 h) labelling plasma NEFA, imTG, imLCAC and im‐non‐esterified FA (imNEFA). Two muscle biopsies (0830 and 1400 h) were performed following 6 h, overlapping, sequential palmitate/oleate tracer infusions. Enrichment of plasma palmitate was ∼15 times greater than enrichment of imTG, imNEFA‐palmitate and im‐palmitoyl‐carnitine. Fatty acid enrichment in LCAC was correlated with imTG and imNEFA; there was a significant correlation between imTG concentrations and imLCAC concentrations in women (r= 0.51, P= 0.005), but not men (r= 0.30, P= 0.11). We estimated that ∼11% of NEFA were stored in imTG. imTG NEFA storage was correlated only with NEFA concentrations (r= 0.52, P= 0.004) in women and with (r= 0.45, P= 0.02) in men. At rest, plasma NEFA are trafficked largely to imTG before they enter LCAC oxidative pools; thus, imTG are an important, central pool that regulates the delivery of fatty acids to the intracellular environment. Factors relating to plasma NEFA storage into imTG differ in men and women.

Effect of pioglitazone on biochemical indices of non-alcoholic fatty liver disease in upper body obesity

BACKGROUND & AIMS The aim of our study is to report our observations on the change in liver function tests of volunteers receiving pioglitazone as part of a study of its effects on fatty acid metabolism. Treatment with other thiazolidinediones has been reported to ameliorate non-alcoholic fatty liver disease (NAFLD) in obese and diabetic humans, but whether pioglitazone has similar effects has not been reported. METHODS Five of 20 upper body obese volunteers (10 men, 10 premenopausal women) had abnormal baseline liver enzymes (3 had ultrasonographic evidence of hepatic steatosis). All volunteers were treated with 30 mg pioglitazone per day for 18 +/- 0.4 weeks. Body composition, blood lipids, and insulin sensitivity (intravenous glucose tolerance test) were assessed at baseline and after pioglitazone treatment. RESULTS During pioglitazone treatment, the liver enzyme abnormalities uniformly improved in subjects with evidence of NAFLD, primarily during the first 2 months. Some parameters of insulin sensitivity improved when measured after 18 weeks of pioglitazone treatment. Liver function tests remained normal in the 15 volunteers without evidence of NAFLD. CONCLUSIONS Liver function studies improved in obese volunteers with NAFLD during pioglitazone treatment. Although the nature of our observations does not prove a cause and effect relationship between pioglitazone treatment and improvement in liver enzymes, the time course and magnitude of improvement we observed may facilitate future research into thiazolidinedione treatment of NAFLD.

Hyperinsulinemia and skeletal muscle fatty acid trafficking

We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults (n = 41) received intravenous infusions of [U-¹³C]palmitate (0400-0900 h) and [U-¹³C]oleate (0800-1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU·kg fat-free mass⁻¹·min⁻¹) clamp (0800-1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-¹³C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning (r = 0.38, P = 0.02) and afternoon (r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG-oleate during hyperinsulinemia were ~1/10th of that observed in the previous saline control studies (P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater (P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin.

LONG-TERM, SUSTAINED, LIFESTYLE-INDUCED WEIGHT LOSS IN SEVERE OBESITY: THE GET-ReAL PROGRAM

OBJECTIVE To study the long-term effectiveness of a patient-centered, multidisciplinary lifestyle intervention treatment in patients medically eligible for bariatric surgery. METHODS Using a case-control study design, we compared treatment results for 98 adults (mean body mass index [BMI], 44.2 kg/m(2)) with the outcomes of 148 controls (mean BMI, 43.0 kg/m(2)) receiving standard care. The approach included a phased triage for inclusion, followed by 12 lifestyle intervention group sessions alternating with individual visits for behavior, diet, and exercise instructions. RESULTS At 2 years, weight loss averaged 15.3 ± 1.4 kg (P<.0010) (12 ± 1% of initial body weight [IBW], P<.001; 21 ± 2% of excess body weight [EBW], P<.001) in an intention-to-treat (ITT) analysis; in completers, weight loss was 18.8 ± 1.5 kg (P<.001) (15 ± 1% IBW, P<.001; 26 ± 3% EBW, P<.001). A total of 42 patients lost ≥10% IBW. Controls remained weight stable (P = .35); 3% lost ≥10% IBW. Patients achieving weight loss that would be considered satisfactory for bariatric surgery included 20% who achieved ≥35% EBW loss, 29% who achieved a BMI <35 kg/m(2) (if starting BMI <50 kg/m(2)) or BMI <40 kg/m(2) (if starting BMI ≥50 kg/m(2)), and 37% who achieved EBW loss ≤50%. These values for completers were 31, 39, and 48%, respectively. In the 55 patients starting the program ≥4 years ago, weight loss maintenance of 12 ± 1% IBW (ITT, 16 ± 1% in completers) was observed. CONCLUSION Substantial nonsurgical weight loss, maintained at 2 to 4 years, is achievable in severely obese patients using comprehensive lifestyle approaches; the efficacy/safety trade-off in obesity treatment is an important consideration in interpreting these results.