Subcutaneous adipose tissue from obese and lean adults does not release hepcidin in vivo.

Hepcidin is the main regulator of systemic iron homeostasis and is primarily produced by the liver but is also expressed, at the mRNA-level, in periphery tissues including the subcutaneous and visceral adipose tissue. Obesity is associated with elevated hepcidin concentrations and iron depletion suggesting that the exaggerated fat mass in obesity could contribute significantly to circulating hepcidin levels consequently altering iron homeostasis. The objective of this study was to determine if abdominal subcutaneous adipose tissue (AbScAT) releases hepcidin in vivo and if release is modified by obesity. Arterio-venous differences in concentrations of hepcidin were measured across AbScAT in 9 obese and 9 lean adults. Overall (n = 18), mean plasma hepcidin concentrations were significantly higher in arterialized compared to AbScAT venous samples [mean difference (arterialized-AbScAT venous plasma hepcidin) = 4.9 ± 9.6 ng/mL, P = 0.04]. Net regional release was not calculated because mean venous plasma hepcidin concentrations were lower than mean arterialized concentrations indicating no net release. Significant correlations between AbScAT venous and arterialized plasma hepcidin concentrations with anthropometric variables were not observed. Findings from this vein drainage study suggest there is no net release of hepcidin from the AbScAT depot and thereby no ability to signal systemically, even in obesity.

Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?

OBJECTIVE: Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat. RESEARCH DESIGN AND METHODS: To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10). RESULTS: Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function. CONCLUSIONS: Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

Regulation of subcutaneous adipose tissue blood flow is related to measures of vascular and autonomic function.

Appropriate blood vessel function is important to cardiovascular health. Adipose tissue plays an important role in metabolic homoeostasis, and subcutaneous abdominal ATBF (adipose tissue blood flow) is responsive to nutritional stimuli. This response is impaired in obesity, suggesting parallels with endothelial function. In the present study, we assessed whether regulation of ATBF is related to the regulation of endothelial function, assessed by FMD (flow-mediated vasodilatation) of the brachial artery. Impaired FMD is a marker of atherosclerotic risk, so we also assessed relationships between ATBF and a marker of atherosclerosis, common carotid artery IMT (intima-media thickness). As ATBF is responsive to sympatho-adrenal stimuli, we also investigated relationships with HRV (heart rate variability). A total of 79 healthy volunteers (44 female) were studied after fasting and after ingestion of 75 g of glucose. FMD, fasting ATBF and the responsiveness of ATBF to glucose were all negatively related to BMI (body mass index), confirming the adverse cardiovascular effects of adiposity. FMD was related to fasting ATBF (rs=0.32, P=0.008) and, at least in males, this relationship was independent of BMI (P=0.02). Common carotid artery IMT, measured in a subset of participants, was negatively related to fasting ATBF [rs=-0.51, P=0.02 (n=20)]. On the other hand, ATBF responsiveness to glucose had no relationship with either FMD or IMT. In multiple regression models, both fasting and stimulated ATBF had relationships with HRV. In conclusion, our results show that the regulation of ATBF has features in common with endothelial function, but also relationships with autonomic cardiovascular control as reflected in HRV.

Development of an arterio-venous difference method to study the metabolic physiology of the femoral adipose tissue depot.

Gluteofemoral adipose tissue (AT) has interesting positive associations with metabolic health, yet little is known of its metabolic physiology. Here, we describe a technique for cannulation of a vein draining the femoral fat depot. Using ultrasound guidance, a cannula was introduced into a superficial branch of the great saphenous vein. We also obtained arterialized blood and, for comparison, blood representing drainage from forearm muscle and from subcutaneous abdominal AT. We measured appropriate biomarkers of skeletal muscle (creatinine) and AT (nonesterified fatty acids (NEFAs), glycerol, leptin) drainage. Blood obtained in this way from the saphenous vein did not show creatinine release (creatinine concentration 100.5 +/- 0.4%, mean +/- s.e.m., of that in arterialized blood), whereas creatinine concentrations in blood draining forearm muscle averaged 121 +/- 1% of those in arterialized blood. Fatty acid release from the tissue drained was suppressed after feeding and increased during beta-adrenergic stimulation. We also demonstrated leptin secretion. These findings suggest that blood so obtained is representative of AT drainage with little apparent contribution of skeletal muscle. We believe this technique will facilitate physiological studies of a lower-body fat depot in humans.

Fasted to fed trafficking of Fatty acids in human adipose tissue reveals a novel regulatory step for enhanced fat storage.

CONTEXT: Absence or excess of adipose tissue are both associated with metabolic complications, implying the importance of well-functioning adipose tissue present in normal amounts. Adipose tissue sequesters dietary fat and thus protects other tissues from excess fat exposure, especially after meals. OBJECTIVE: The objective of the study was the use of an integrative physiological technique to quantify trafficking of fatty acids (FAs) in adipose tissue over a 24 h period. METHODS: Adipose tissue FA handling was studied in response to three meals in eight healthy men by the combination of arteriovenous blood sampling, tissue blood flow, and specific labeling of FA tracing of exogenous and endogenous fat by stable isotope methodology. RESULTS: The efficiency of adipose tissue FA uptake increased robustly with each meal. Chylomicron-triglyceride was the dominating source of FA. Adipose tissue fractional extraction of chylomicron-triglyceride increased from 21 +/- 4 to 47 +/- 8% (P = 0.03) between the first and last meal. Although adipose tissue lipoprotein lipase action increased with time (2-fold), there was an even greater increase in FA reesterification (3-fold), which led to a reduced spillover of chylomicron-derived FA, from 77 +/- 15 to 34 +/- 7% (P = 0.04) comparing the end of the first and the third meal period. Increased uptake of very low-density lipoprotein-derived FA was observed, but spillover of very low-density lipoprotein-derived FA was seen only in the fasting state. CONCLUSION: Human adipose tissue has a significant potential to up-regulate fat storage during a normal day that goes beyond increased lipoprotein lipase activation. The adaptation toward increasing fat storage may provide an explanation for the beneficial properties of normal amounts of adipose tissue.

Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism.

BACKGROUND: Resistant starch may modulate insulin sensitivity, although the precise mechanism of this action is unknown. OBJECTIVE: We studied the effects of resistant starch on insulin sensitivity and tissue metabolism. DESIGN: We used a 4-wk supplementation period with 30 g resistant starch/d, compared with placebo, in 10 healthy subjects and assessed the results by using arteriovenous difference methods. RESULTS: When assessed by euglycemic-hyperinsulinemic clamp, insulin sensitivity was higher after resistant starch supplementation than after placebo treatment (9.7 and 8.5 x 10(-2) mg glucose x kg(-1) x min(-1) x (mU insulin/L)(-1), respectively; P = 0.03); insulin sensitivity during the meal tolerance test (MTT) was 33% higher (P = 0.05). Forearm muscle glucose clearance during the MTT was also higher after resistant starch supplementation (P = 0.03) despite lower insulin concentrations (P = 0.02); glucose clearance adjusted for insulin was 44% higher. Subcutaneous abdominal adipose tissue nonesterified fatty acid (NEFA; P = 0.02) and glycerol (P = 0.05) release were lower with resistant starch supplementation, although systemic NEFA concentrations were not significantly altered. Short-chain fatty acid concentrations (acetate and propionate) were higher during the MTT (P = 0.05 and 0.01, respectively), as was acetate uptake by adipose tissue (P = 0.03). Fasting plasma ghrelin concentrations were higher with resistant starch supplementation (2769 compared with 2062 pg/mL; P = 0.03), although postprandial suppression (40-44%) did not differ significantly. Measurements of gene expression in adipose tissue and muscle were uninformative, which suggests effects at a metabolic level. The resistant starch supplement was well tolerated. CONCLUSION: These results suggest that dietary supplementation with resistant starch has the potential to improve insulin sensitivity. Further studies in insulin-resistant persons are needed.