A Human Randomized Controlled Trial Comparing Metabolic Responses to Single and Repeated Hypoglycemia in Type 1 Diabetes.

AIMS: Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counter-regulatory responses to hypoglycemia. Our study was designed to test whether (1) the metabolic responses and insulin sensitivity are impaired, and (2) whether they are affected by short-lived antecedent hypoglycemia in participants with T1D. MATERIALS AND METHODS: In a randomized, crossover, 2x2 factorial design, 9 male participants with T1D and 9 comparable control participants underwent 30 minutes of hypoglycemia (p-glucose < 2.9 mmol/L) followed by a euglycemic clamp on 2 separate interventions: with and without 30 minutes of hypoglycemia the day before the study day. RESULTS: During both interventions insulin sensitivity was consistently lower, while counter-regulatory hormones were reduced, with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5- to 10-fold increased ketone body concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake, and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue phosphatase and tensin homolog (PTEN) content, hormone-sensitive lipase (HSL) phosphorylation, and muscle glucose transporter type 4 (GLUT4) content were decreased compared with controls. And antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity. CONCLUSIONS: Participants with T1D displayed insulin resistance and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact and ketogenic responses were amplified. We observed subtle alterations of intracellular signaling and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.

Fat distribution in short-stature children born small for gestational age.

BACKGROUND: Children born small for gestational age (SGA) with catch-up growth are at high risk for developing obesity; however, the characteristics of body composition, especially fat distribution, before and after growth hormone (GH) treatment in SGA children without catch-up growth remains largely unknown. METHODS: Anthropometric characteristics, body composition by dual-energy X-ray absorption, and fat distribution by computed tomography at the umbilical level were examined in 27 prepubertal short-stature children born SGA before and 1 year after GH treatment. RESULTS: Before GH treatment, short-stature SGA children had lean phenotypes, and both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were significantly lower than the age- and sex-matched Japanese reference values. Growth hormone treatment significantly increased height standard deviation scores (SDS), without affecting body mass index SDS. Percentage fat mass decreased with GH treatment; however, fat mass was not altered. Both VAT and SAT were significantly lower than the reference values after GH treatment. The ratio of VAT over SAT significantly increased by GH treatment. CONCLUSIONS: Both VAT and SAT were within or below the age- and sex-matched Japanese reference values in short-stature children born SGA before and after GH treatment, indicating that GH treatment may not have unfavorable effects on adiposity in short-stature children born SGA, although it may alter fat distribution.

A randomized double-blind trial evaluating the efficacy and tolerability of topical body treatment with TriHex Technology® combined with abdomen cryolipolysis or radiofrequency procedures.

BACKGROUND: Nonsurgical fat reduction procedures using cryolipolysis and radiofrequency are among the most popular noninvasive aesthetic procedures. In a previous study, TransFORM Body Treatment (TFB) with TriHex Technology® (ALASTIN® Skincare) improved the contour and reduced skin laxity following cryolipolysis of the arms. This product is formulated using a combination of peptides and other active ingredients designed to stimulate the autophagic breakdown of lipid droplets and expedite the apoptotic process after fat reduction procedures. AIMS: To assess the changes in abdominal volume after application of TFB for 12 weeks following cryolipolysis and radiofrequency procedures. METHODS: Following abdominal cryolipolysis or radiofrequency therapy, the subjects (N = 15) received TFB product and placebo and were randomly assigned to apply to the right or left sides of the abdomen for 12 weeks. Using 3-dimensional digital imaging analysis, subjects were evaluated at 4, 8, and 12 weeks posttreatment. RESULTS: Topical TFB resulted in increased volume loss, which was greater than that for placebo at weeks 4 (P = .0511), 8 (P = .0238), and 12 (P = .0078), respectively, and statistically significant at weeks 8 and 12. There were no reported adverse events. CONCLUSION: In this study, Topical application of TFB significantly increased adipose volume loss and improved clinical outcomes of nonsurgical fat reduction procedures.

Histological Analysis of the Effect of ATX-101 (Deoxycholic Acid Injection) on Subcutaneous Fat: Results From a Phase 1 Open-Label Study.

BACKGROUND: ATX-101 is approved for submental fat reduction. OBJECTIVE: To characterize the histological effect of ATX-101 injection into subcutaneous fat. METHODS: This Phase 1 open-label study enrolled 14 adults to receive injections of ATX-101 into abdominal fat at varying concentrations (0.5%, 1.0%, 2.0%, or 4.0%), volumes (0.2 or 0.4 mL), spacing (0.7, 1.0, or 1.5 cm), and time points before scheduled abdominoplasty (1, 3, 7, or 28 days). During abdominoplasty, tissue was excised and preserved for histology. RESULTS: All injection paradigms resulted in histological changes confined to the subcutaneous layer, which were more prominent at higher concentrations and independent of volume and spacing. Key features at Day 1 after injection were adipocytolysis, blood vessel injury, neutrophilic inflammation, and lysis of locally present neutrophils. At Day 3, inflammation was reduced versus Day 1, and hemorrhage and lipid lake formation (at higher concentrations) were observed. Day 7 samples exhibited prominent adipocytolysis, mild inflammation, lipid-laden macrophages in the septae, and repair of vascular injury. At Day 28, inflammation was largely resolved and prominent features were septal thickening, neovascularization, and atrophy of fat lobules. CONCLUSION: Subcutaneous injection of ATX-101 induces adipocytolysis and local inflammation with septal thickening and resolution of inflammation by 28 days after injection.

Adipose tissue oxylipin profiles vary by anatomical site and are altered by dietary linoleic acid in rats.

Dietary PUFA and their effects on adipose tissue have been well studied, but oxylipins, the oxygenated metabolites of PUFA, have been sparsely studied in adipose tissue. To determine the oxylipin profile and to examine their potential importance in various adipose sites, female and male rats were provided control, high linoleic acid (LA), or high LA and high α-linolenic acid (LA + ALA) diets for six weeks. Analysis of gonadal (GAT), mesenteric (MAT), perirenal (PAT), and subcutaneous adipose tissues (SAT) revealed higher numbers of oxylipins in MAT and SAT, primarily due to 20-22 carbon cytochrome P450 oxylipins, as well as metabolites of cyclooxygenase derived oxylipins. LA oxylipins made up 75-96% of the total oxylipin mass and largely determined the total relative amounts between depots (GAT > MAT > PAT > SAT). However, when the two most abundant LA oxylipins (TriHOMEs) were excluded, MAT had the highest mass of oxylipins and exhibited the most sex differences. These differences existed despite comparable PUFA composition between depots. Dietary LA increased oxylipins derived from n-6 PUFA, and the addition of ALA generally returned n-6 PUFA oxylipins to levels similar to control and elevated some n-3 oxylipins. These data on oxylipin profiles in adipose depots from different anatomical sites and the effects of diet and sex provide fundamental knowledge that will aid future studies investigating the physiological effects of adipose tissue.

Does non-activated platelet-rich plasma (PRP) enhance fat graft outcome? An assessment with 3D CT-scan in mice.

BACKGROUND: The adjunction of autologous platelet-rich plasma (PRP) is emerging as a promising approach to enhance the long-term survival of fat grafting, but there are still insufficient data on its efficacy. The aim of this in vivo study was to assess the effect of the addition of non-activated PRP on fat graft outcome. METHODS: Human adipose tissue mixed with 20% of non-activated PRP was injected under the scalp skin of nude Balb/cAnNRj mice and compared to grafted fat mixed with 20% of saline. The fat graft volume was analyzed by a computed tomography scan until day 90 and immunohistochemistry was then performed to assess adipocyte viability and graft revascularization. RESULTS: At day 90, the volume of fat graft was not enhanced by PRP compared to the saline control group. However, immunohistochemistry showed that PRP significantly increased the fat graft area occupied by intact adipocytes compared to the saline group (72.66% vs. 60.78%, respectively; p < 0.05). Vascularity was also significantly higher in the PRP group compared to the control group (6695 vs. 4244 CD31+ cells/µm2, respectively; p < 0.05). CONCLUSION: The adjunction of non-activated-PRP to fat grafts significantly increased adipocyte viability and tissue vascularity. However, in contrast to other studies adding activated-PRP, non-activated-PRP did not increase residual fat graft volume until day 90. Further studies are therefore needed to understand whether PRP has a positive effect on fat graft volume. As 3D computed tomography scan is a reproducible and precise technique, it should be used to analyze fat graft volume changes over time.

Mechanisms of the antilipolytic response of human adipocytes to tyramine, a trace amine present in food.

Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions. Lipolytic activity was determined in adipocytes from human subcutaneous abdominal adipose tissue. Glycerol release was increased by a fourfold factor with classical lipolytic agents (1 µM isoprenaline, 1 mM isobutylmethylxanthine) while the amine was ineffective from 0.01 to 100 µM and hardly stimulatory at 1 mM. Tyramine exhibited a partial antilipolytic effect at 100 µM and 1 mM, which was similar to that of insulin but weaker than that obtained with agonists at purinergic A1 receptors, α2-adrenoceptors, or nicotinic acid receptors. Gi-protein blockade by Pertussis toxin abolished all these antilipolytic responses save that of tyramine. Indeed, tyramine antilipolytic effect was impaired by MAO-A inhibition. Tyramine inhibited protein tyrosine phosphatase activities in a manner sensitive to ascorbic acid and amine oxidase inhibitors. Thus, millimolar tyramine restrained lipolysis via the hydrogen peroxide it generates when oxidized by MAO. Since tyramine plasma levels have been reported to reach 0.2 µM after ingestion of 200 mg tyramine in healthy individuals, the direct effects we observed in vitro on adipocytes could be nutritionally relevant only when the MAO-dependent hepato-intestinal detoxifying system is overpassed.

Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus.

AIMS: We examined dapagliflozin-induced changes in liver fat accumulation. METHODS: We prospectively recruited Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM) [hemoglobin A1c (HbA1c) >7.0%]. Dapagliflozin (5 mg/day) or non-sodium glucose cotransporter 2 inhibitors (SGLT2i) was added to the patients' treatment regimen for 6 months. Changes in liver fat accumulation were assessed by the liver-to-spleen (L/S) attenuation ratio using abdominal computed tomography (CT). RESULTS: This study enrolled 55 Japanese T2DM patients. The L/S ratio significantly increased in the dapagliflozin group compared with the non-SGLT2i group. Abdominal subcutaneous fat area (SFA), visceral fat area, total fat area assessed by abdominal CT, aspartate aminotransferase, alanine aminotransferase (ALT), and γ-glutamyl transpeptidase decreased significantly only in the dapagliflozin group. Changes in the L/S ratio showed a significant negative relationship with changes in abdominal SFA, ALT, and non-esterified fatty acid. In sub-group analyses of non-insulin users, hepatic insulin extraction was assessed by the plasma C-peptide-to-insulin ratio, which was significantly increased in the dapagliflozin group but not in the non-SGLT2i group. CONCLUSION: In patients with inadequately controlled T2DM, additional dapagliflozin-treatment significantly reduced the liver fat accumulation associated with a decrease in abdominal SFA.

Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity.

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

Subcutaneous infiltration of carbon dioxide (carboxytherapy) for abdominal fat reduction: A randomized clinical trial.

BACKGROUND: Noninvasive fat removal is preferred because of decreased downtime and lower perceived risk. It is important to seek new noninvasive fat removal treatments that are both safe and efficacious. OBJECTIVE: To assess the extent to which carboxytherapy, which is the insufflation of carbon dioxide gas into subcutaneous fat, results in reduction of fat volume. METHODS: In this randomized, sham-controlled, split-body study, adults (body mass index, 22-29 kg/m2) were randomized to receive 5 weekly infusions of 1000 cm3 of CO2 to 1 side of the abdomen, and 5 sham treatments to the contralateral side. The primary outcome measures were ultrasound measurement of fat layer thickness and total circumference before and after treatment. RESULTS: A total of 16 participants completed the study. Ultrasound measurement indicated less fat volume on the side treated with carboxytherapy 1 week after the last treatment (P = .011), but the lower fat volume was not maintained at 28 weeks. Total circumference decreased nominally but not significantly at week 5 compared with baseline (P = .0697). Participant body weights did not change over the entire course of the study (P = 1.00). LIMITATIONS: Limitations included modest sample size and some sources of error in the measurement of circumference and fat layer. CONCLUSION: Carboxytherapy provides a transient decrease in subcutaneous fat that may not persist. Treatment is well tolerated.

Phytol stimulates the browning of white adipocytes through the activation of AMP-activated protein kinase (AMPK) α in mice fed high-fat diet.

Stimulating the browning of white adipocytes contributes to the restriction of obesity and related metabolic disorders. This study aimed to investigate the browning effects of phytol on mice inguinal subcutaneous white adipose tissue (iWAT) and explore the underlying mechanisms. Our results demonstrated that phytol administration decreased body weight gain and iWAT index, and stimulated the browning of mice iWAT, with the increased expression of brown adipocyte marker genes (UCP1, PRDM16, PGC1α, PDH, and Cyto C). In addition, phytol treatment activated the AMPKα signaling pathway in mice iWAT. In good agreement with the in vivo findings, the in vitro results showed that 100 µM phytol stimulated brown adipogenic differentiation and formation of brown-like adipocytes in the differentiated 3T3-L1 by increasing the mitochondria content and oxygen consumption, and promoting mRNA and/or protein expression of brown adipocyte markers (UCP1, PRDM16, PGC1α, PDH, Cyto C, Cidea and Elovl3) and beige adipocyte markers (CD137 and TMEM26). Meanwhile, phytol activated the AMPKα signaling pathway in the differentiated 3T3-L1. However, the inhibition of AMPKα with Compound C totally abolished phytol-stimulated brown adipogenic differentiation and formation of brown-like adipocytes. In conclusion, these results showed that phytol stimulated the browning of mice iWAT, which was coincident with the increased formation of brown-like adipocytes in the differentiated 3T3-L1, and appeared to be primarily mediated by the AMPKα signaling pathway. These data provided new insight into the role of phytol in regulating the browning of WAT and suggested the potential application of phytol as a nutritional intervention for the restriction of obesity and related metabolic disorders.

Effect of liraglutide on dietary lipid-induced insulin resistance in humans.

AIMS: To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet-induced insulin resistance. METHODS: In a randomized placebo-controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24-hour SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants underwent ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle. RESULTS: Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA diet (by 50%, 25% and 9%, respectively), and the SFA diet increased plasma glucose during the IST (by 36%; all P < .01 vs placebo). The SFA diet-induced impairment of vasodilation on placebo (-9.4% vs baseline; P < .01) was ameliorated by liraglutide (-4.8%; P = .1 vs baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease; P < .01 vs placebo) and increased 5'AMP-activated protein kinase (AMPK) phosphorylation (50% vs -3%; P = .04 vs placebo). CONCLUSIONS: Liraglutide blunted the SFA-enriched diet-induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.

Chronic low-dose glucocorticoid treatment increases subcutaneous abdominal fat, but not visceral fat, of male Wistar rats.

AIM: Most studies developed to investigate the effects of glucocorticoids chronic treatment on white adipose tissue uses high doses of these hormones. This study analyzes some effects of a chronic, continuous and steady infusion of low-dose hydrocortisone and the relationship with lipid accumulation in white adipose depots in rats. MAIN METHODS: Nineteen male Wistar rats were divided into control (CON) and cortisol (CORT) groups. Along six weeks CORT group received continuous infusion of 0.6mg/kg/day of hydrocortisone, while CON group received saline. After euthanasia, subcutaneous and visceral (retroperitoneal and mesenteric) fat pads were excised, weighted and analyzed for: lipogenic enzymes activity; molecular changes of 11-hydroxysteroid dehydrogenase type 1 (11ßHSD1) enzyme; enzymes involved in lipid uptake, incorporation, and metabolism and in fatty acids esterification. Besides, morphometric cell analysis was performed. KEY FINDINGS: CORT group showed increased triglycerides, changes in lipoprotein profile and 26,8% increment in central subcutaneous (SC) mass, while visceral fat pads masses remained unchanged. Adipocytes from SC, only, presented increased fatty acid synthase, ATP-citrate lyase and glucose-6-phosphate dehydrogenase activity, in addition to reduced AMP-activated protein kinase and 11ßHSD1 enzymes content. SIGNIFICANCE: Chronic low-dose hydrocortisone treatment consequences seem to be different from those commonly seen in long term hypercortisolism. While high doses promote lipid accumulation in visceral depots, a low dose showed an increase in central SC depot only. This appears to involve an increment in lipid storage and in de novo lipogenesis enzymes activity.

Subcutaneous Adipocyte Lipolysis Contributes to Circulating Lipid Levels.

OBJECTIVE: Fatty acids released via fat cell lipolysis can affect circulating lipid levels. However, the contribution of different lipolysis measures in adipose tissue is unknown and was presently examined in isolated subcutaneous adipocytes. APPROACH AND RESULTS: One thousand and sixty-six men and women were examined for lipolysis regulation in subcutaneous abdominal fat cells. Results were compared with fasting plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C) and triglycerides. Spontaneous (basal) lipolysis and the effects of the major hormones stimulating (catecholamines and natriuretic peptides) and inhibiting lipolysis (insulin) were examined. Several statistically significant (P<0.0001) correlations between the different lipolysis parameters and plasma lipids were observed. However, physiologically relevant correlations (adjusted r2≥0.05) were only evident between basal or insulin-inhibited lipolysis and plasma triglycerides or HDL-C. Together, these lipolysis measures explained 14% of the variation in triglycerides or HDL-C, respectively. In comparison, a combination of established factors associated with variations in plasma lipids, that is, age; body mass index; waist circumference; waist-to-hip ratio; sex; nicotine use; fat cell volume; and pharmacotherapy against diabetes mellitus; hypertension; or hyperlipidemia explained 17% and 28%, respectively, of the variations in plasma triglycerides and HDL-C. CONCLUSIONS: Subcutaneous fat cell lipolysis is an important independent contributor to interindividual variations in plasma lipids. High spontaneous lipolysis activity and resistance to the antilipolytic effect of insulin associate with elevated triglyceride and low HDL-C concentrations. Thus, although several other factors also play a role, subcutaneous adipose tissue may have a causal influence on dyslipidemia.

GH administration decreases subcutaneous abdominal adipocyte size in men with abdominal obesity.

OBJECTIVE: To investigate the effects of short-term GH administration on abdominal subcutaneous adipocyte size and CT attenuation in men with abdominal obesity. DESIGN: 6-week, randomized, double-blind, placebo-controlled study of GH (starting dose 2µg/kg/d) vs placebo of 15 abdominally obese men (mean age: 34±6years; mean BMI: 37.7±6.1kg/m2, mean IGF-1 SDS: -1.9±0.5) who underwent abdominal subcutaneous adipose tissue (SAT) aspirations to determine adipocyte size, CTs for body composition and measures of glucose tolerance at baseline and 6weeks. GH dosing was titrated to target IGF-1 levels in the upper normal age-appropriate range. RESULTS: GH administration decreased subcutaneous abdominal adipocyte size compared to placebo. Adipocyte size was positively associated with 120-min glucose and HOMA-IR and inversely associated with peak-stimulated GH and CT attenuation. CT attenuation of SAT was inversely associated with 120-min glucose and HOMA-IR and increased following GH administration. CONCLUSION: In men with abdominal obesity, subcutaneous abdominal adipocyte size is positively associated with measures of impaired glucose tolerance and administration of GH at doses that raise IGF-1 levels within the normal range, decreases abdominal subcutaneous adipocyte size, suggesting that GH administration improves the health of adipose tissue. Clinical trials number: NCT00131378.

Deletion of interleukin 1 receptor-associated kinase 1 (Irak1) improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle.

Chronic inflammation may contribute to insulin resistance via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) mediates pro-inflammatory signaling via IL-1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male Irak1 null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice (versus WT) had substantially improved glucose tolerance (assessed by the intraperitoneal glucose tolerance test (IPGTT)). As assessed with the hyperinsulinemic euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the Irak1 k/o mice on chow diet, but the Irak1 deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (± insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in Irak1 k/o mice in vivo Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from Irak1 k/o mice ex vivo In conclusion, Irak1 deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice.

Acute Hypercortisolemia Exerts Depot-Specific Effects on Abdominal and Femoral Adipose Tissue Function.

CONTEXT: Glucocorticoids have pleiotropic metabolic functions, and acute glucocorticoid excess affects fatty acid metabolism, increasing systemic lipolysis. Whether glucocorticoids exert adipose tissue depot-specific effects remains unclear. OBJECTIVE: To provide an in vivo assessment of femoral and abdominal adipose tissue responses to acute glucocorticoid administration. DESIGN AND OUTCOME MEASURES: Nine healthy male volunteers were studied on two occasions, after a hydrocortisone infusion (0.2 mg/kg/min for 14 hours) and a saline infusion, respectively, given in randomized double-blind order. The subjects were studied in the fasting state and after a 75-g glucose drink with an in vivo assessment of femoral adipose tissue blood flow (ATBF) using radioactive xenon washout and of lipolysis and glucose uptake using the arteriovenous difference technique. In a separate study (same infusion design), eight additional healthy male subjects underwent assessment of fasting abdominal ATBF and lipolysis only. Lipolysis was assessed as the net release of nonesterified fatty acids (NEFAs) from femoral and abdominal subcutaneous adipose tissue. RESULTS: Acute hypercortisolemia significantly increased basal and postprandial ATBF in femoral adipose tissue, but the femoral net NEFA release did not change. In abdominal adipose tissue, hypercortisolemia induced substantial increases in basal ATBF and NEFA release. CONCLUSIONS: Acute hypercortisolemia induces differential lipolysis and ATBF responses in abdominal and femoral adipose tissue, suggesting depot-specific glucocorticoid effects. Abdominal, but not femoral, adipose tissue contributes to the hypercortisolemia-induced systemic NEFA increase, with likely contributions from other adipose tissue sources and intravascular triglyceride hydrolysis.