Citations

OBJECTIVE— We assessed the direct (VLDL-triglycerides [VLDL-TG] independent) storage of circulating free fatty acids (FFAs) in visceral and subcutaneous fat in postabsorptive women. RESEARCH DESIGN AND METHODS— Twelve women (BMI 29.6 ± 6.6 kg/m2) received an identical, intravenous bolus dose of [1-14C]oleate followed by timed subcutaneous fat biopsies (abdominal and femoral) and then omental fat biopsy during tubal ligation surgery. Regional fat masses were assessed by combining dual-energy X-ray absorptiometry and computed tomography scanning. Separately, we assessed the fraction of FFA tracer entering VLDL-TG over the time representing the delay in collecting omental fat. RESULTS— Site-specific fat specific activity (SA) (dpm/g lipid) decreased as a function of fat mass in both upper-body subcutaneous (UBSQ) and visceral fat depots. These patterns are consistent with dilution of a relatively fixed amount of FFA tracer within progressively greater amounts of fat. Interestingly, femoral SA did not vary as a function of lower-body subcutaneous (LBSQ) fat mass. [1-14C]oleate storage per million LBSQ adipocytes was positively associated with LBSQ fat mass, but no significant relationships were observed in UBSQ or visceral fat depot. The fraction of [1-14C]oleate stored in UBSQ, LBSQ, and visceral fat was 6.7 ± 3.2, 4.9 ± 3.4, and 1.0 ± 0.3%, respectively. Only ∼4% of the tracer traversed VLDL-TG over 9.5 h. CONCLUSIONS— The increase in FFA tracer storage per adipocyte as a function of LBSQ fat mass implies that LBSQ adipocytes, in contrast to UBSQ and omental adipocytes, store more FFA in women with greater adiposity. The direct FFA storage pathway might play a role in favoring lower-body fat accumulation in women.

OBJECTIVE—Differential meal fat uptake into adipose tissue depots may be a determinant of body fat distribution. RESEARCH DESIGN AND METHODS—We used the meal fat tracer/adipose tissue biopsy approach to compare the effects of meal fat content on the fat uptake into visceral and upper and lower body subcutaneous fat depots in 21 premenopausal women. [3H]triolein was used to trace the fate of fatty acids from a normal-fat or high-fat meal. RESULTS—The proportion of dietary fat uptake into the three depots did not differ between meals; visceral fat accounted for only ∼5% of meal fat disposal irrespective of visceral fat mass. For the women consuming the normal-fat meal, the uptake of meal fatty acid into femoral fat (milligrams meal fat per gram lipid) increased as a function of leg fat mass (r = 0.68, P < 0.05), which we interpret as increased efficiency of uptake. The opposite pattern was seen in omental fat with the normal-fat meal and in all depots after the high-fat meal. For both meals, ∼40% of meal fat was oxidized (3H2O production) after 24 h. CONCLUSIONS—We conclude that greater thigh adipose tissue in women is associated with greater efficiency of meal fat storage under conditions of energy balance, whereas the opposite is seen with visceral fat. These findings imply that different mechanisms may regulate fatty acid uptake in different depots, which may in turn impact on body fat distribution.

Humans have a large variability in body fat distribution, which has tremendous implications for metabolic health. Obese individuals with an upper-body-fat distribution have increased health complications such as dyslipidemia, hypertension, insulin resistance, and type 2 diabetes in comparison with lower-body-obese individuals. Additionally, females have more body fat, a greater proportion of fat in their lower body, and much less visceral fat than do lean males at the same body mass index. The reasons for these differences in body fat distribution have not been clearly identified but could be important. Herein we review what has been learned about regional differences in triglyceride storage capacity and lipolysis as they relate to the causes and consequences of regional fat accumulation. Both sex and site differences in regional fat storage have been described. In contrast, with the exception of variations between men and women in the contribution of visceral adipose tissue to hepatic FFA delivery, most studies have failed to show important sex differences in regional lipolysis in vivo.

OBJECTIVE—We sought to determine whether, and if so the mechanism by which, testosterone replacement improves carbohydrate tolerance. RESEARCH DESIGN AND METHODS—Fifty-five elderly men with relative testosterone deficiency ingested a labeled mixed meal and underwent a frequently sampled labeled intravenous glucose tolerance test before and after either placebo or treatment with testosterone patch (5 mg/day) for 2 years. RESULTS—Despite restoring bioavailable testosterone to values observed in young men, the change (24 months minus baseline values) in fasting and postprandial glucose, insulin, and C-peptide concentrations and meal appearance, glucose disposal, and endogenous glucose production were virtually identical to those observed after 2 years of placebo. The change over time in insulin and C-peptide concentrations post–intravenous glucose injection also did not differ. Furthermore, the change over time in insulin action and glucose effectiveness (measured with the unlabeled and labeled “oral” and “intravenous” minimal models), as well as insulin secretion and hepatic insulin clearance (measured with the C-peptide model), did not differ in the testosterone and placebo groups. CONCLUSIONS—We conclude that 2 years of treatment with testosterone in elderly men does not improve carbohydrate tolerance or alter insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, or the pattern of postprandial glucose metabolism. Thus, testosterone deficiency is unlikely the cause of the age-associated deterioration in glucose tolerance commonly observed in elderly men.

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.

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at ∼8.3 mmol/l and insulin was increased to ∼300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 ± 2.6 vs. 65.0 ± 7.9 μmol · kg−1 · min−1). Whole-body glucose disappearance (37.0 ± 2.2 vs. 70.9 ± 8.7 μmol · kg−1 · min−1; P < 0.001) and leg glucose uptake (24.3 ± 4.2 vs. 59.6 ± 10.0 μmol · kg fat-free mass of the leg−1 · min−1; P < 0.02) were also lower, whereas splanchnic glucose production (8.2 ± 0.8 vs. 4.3 ± 0.7 μmol · kg−1 · min−1; P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting whole- body glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production.

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to ∼1 mmol/l by an 8-h Intralipid/heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match (n = 5, low glycerol) or double (n = 8, high glycerol) the plasma glycerol concentrations observed during the IL/Hep infusion. Glucose was clamped at ∼8.3 mmol/l, and insulin was increased to ∼300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. Leg glucose uptake (21.7 ± 3.5 vs. 48.3 ± 9.3 and 57.8 ± 11.7 μmol · kg−1 leg · min−1) was lower (P < 0.001) during IL/Hep than the low- or high-glycerol infusions, confirming that elevated FFAs caused insulin resistance in muscle. IL/Hep did not alter splanchnic glucose uptake or the contribution of the extracellular direct pathway to UDP-glucose flux. On the other hand, total UDP-glucose flux (13.2 ± 1.7 and 12.5 ± 1.0 vs. 8.1 ± 0.5 μmol · kg−1 · min−1) and flux via the indirect intracellular pathway (8.4 ± 1.2 and 8.1 ± 0.6 vs. 4.8 ± 0.05 μmol · kg−1 · min−1) were greater (P < 0.05) during both the IL/Hep and high-glycerol infusions than the low-glycerol infusion. In contrast, only IL/Hep increased (P < 0.05) splanchnic glucose production, indicating that elevated FFAs impaired the ability of the liver to autoregulate. Splanchnic insulin extraction, directly measured using the arterial and hepatic vein catheters, did not differ (67 ± 3 vs. 71 ± 5 vs. 69 ± 1%) during IL/Hep and high- and low-glycerol infusions. We conclude that elevated FFAs exert multiple effects on glucose metabolism. They inhibit insulin- and glucose-induced stimulation of muscle glucose uptake and suppression of splanchnic glucose production. They increase the contribution of the indirect pathway to glycogen synthesis and impair hepatic autoregulation. On the other hand, they do not alter either splanchnic glucose uptake or splanchnic insulin extraction in nondiabetic humans.

We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 μmol · kg−1 · min−1 while supplemental glucose was given intravenously to clamp glucose at ∼10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at ∼300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was ∼35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes.

Studies were conducted to determine whether regional free fatty acid (FFA) release is differentially regulated by insulin. Systemic, leg, and splanchnic palmitate rate of appearance ([9,10-(3)H]palmitate) was measured in 26 healthy adults using the euglycemic-hyperinsulinemic clamp technique to achieve a physiological range of plasma insulin concentrations. We found that insulin inhibited systemic, leg, and splanchnic palmitate release in a dose-dependent fashion over the range of insulin infused (0-1.0 mU x kg(-1) x min(-1)). Progressive hyperinsulinemia changed the leg from a net producer to a net FFA consumer, whereas the splanchnic bed converted from a net FFA consumer to a net producer. At the 0.5 mU x kg(-1) x min(-1) insulin infusion rate, leg FFA release was almost completely suppressed, whereas even with the 1.0 mU x kg(-1) x min(-1) insulin infusion rate, splanchnic FFA release decreased by only approximately 65% (P < 0.05 leg vs. splanchnic). These results demonstrate the regional heterogeneity of insulin-regulated FFA release in vivo, and indicate that visceral adipose tissue lipolysis is more resistant to insulin suppression than is leg lipolysis in humans.

To examine if postprandial splanchnic/hepatic free fatty acid (FFA) delivery is increased in upper-body (UB) obesity, and to determine the adipose tissue depots responsible for the greater postprandial FFA availability, we measured systemic and regional uptake and release of FFAs ([1-(14)C]palmitate) before and during a 5-h frequent-feeding mixed meal in eight UB and eight lower-body (LB) obese women. Postabsorptive FFA flux and splanchnic FFA delivery were not different in UB and LB obese women; however, postprandial FFA concentrations (257 +/- 45 vs. 81 +/- 12 micromol/l, P < 0.0001), FFA flux (8.5 +/- 1.2 vs. 3.9 +/- 0.8 micromol x kg(-1) fat-free mass x min(-1), P < 0.0001), splanchnic FFA delivery (275 +/- 45 vs. 88 +/- 24 micromol/min, respectively, P < 0.005), and estimated hepatic FFA delivery were greater in UB than LB obese women. Nonsplanchnic UB adipose tissue FFA release was greater in UB than in LB obese women (276 +/- 71 vs. 97 +/- 37 micromol/min, respectively, P < 0.05) and accounted for the greater postprandial FFA availability in UB obesity. Postprandial leg glucose uptake was less in UB than in LB obese women (8.4 +/- 5.1 vs. 22.9 +/- 2.6 micromol x kg(-1) leg fat-free mass x min(-1), P < 0.05). We conclude that the elevated postprandial FFA release observed in UB obese women originates from the nonsplanchnic UB fat, not visceral fat. These results suggest that visceral fat may be a marker for, but not the source of, excess postprandial FFAs in obesity.