bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue
Authors: Stallknecht Bente , Larsen Jens J. , Mikines Kari J. , Simonsen Lene , Bülow Jens , Galbo Henrik
Published: December 2017

Training increases insulin sensitivity of both whole body and muscle in humans. To investigate whether training also increases insulin sensitivity of adipose tissue, we performed a three-step hyperinsulinemic, euglycemic clamp in eight endurance-trained (T) and eight sedentary (S) young men [insulin infusion rates: 10,000 ( step I), 20,000 ( step II), and 150,000 ( step III) μU · min−1 · m−2]. Glucose and glycerol concentrations were measured in arterial blood and also by microdialysis in interstitial fluid in periumbilical, subcutaneous adipose tissue and in quadriceps femoris muscle (glucose only). Adipose tissue blood flow was measured by 133Xe washout. In the basal state, adipose tissue blood flow tended to be higher in T compared with S subjects, and in both groups blood flow was constant during the clamp. The change from basal in arterial-interstitial glucose concentration difference was increased in T during the clamp but not in S subjects in both adipose tissue and muscle [adipose tissue: step I ( n = 8), 0.48 ± 0.18 mM (T), 0.23 ± 0.11 mM (S); step II ( n = 8), 0.19 ± 0.09 (T), −0.09 ± 0.24 (S); step III( n = 5), 0.47 ± 0.24 (T), 0.06 ± 0.28 (S); (T: P < 0.001, S: P > 0.05); muscle: step I ( n = 4), 1.40 ± 0.46 (T), 0.31 ± 0.21 (S); step II ( n = 4), 1.14 ± 0.54 (T), −0.08 ± 0.14 (S); step III( n = 4), 1.23 ± 0.34 (T), 0.24 ± 0.09 (S); (T: P < 0.01, S: P > 0.05)]. Interstitial glycerol concentration decreased faster in T than in S subjects [half-time: T, 44 ± 9 min ( n = 7); S, 102 ± 23 min ( n = 5); P < 0.05]. In conclusion, training enhances insulin sensitivity of glucose uptake in subcutaneous adipose tissue and in skeletal muscle. Furthermore, interstitial glycerol data suggest that training also increases insulin sensitivity of lipolysis in subcutaneous adipose tissue. Insulin per se does not influence subcutaneous adipose tissue blood flow.
The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes
Authors: Penfornis Patrice , Viengchareun Say , Le Menuet Damien , Cluzeaud Françoise , Zennaro Maria-Christina , Lombès Marc
Published: December 2017

By use of targeted oncogenesis, a brown adipocyte cell line was derived from a hibernoma of a transgenic mouse carrying the proximal promoter of the human mineralocorticoid receptor (MR) linked to the SV40 large T antigen. T37i cells remain capable of differentiating into brown adipocytes upon insulin and triiodothyronine treatment as judged by their ability to express uncoupling protein 1 and maintain MR expression. Aldosterone treatment of undifferentiated cells induced accumulation of intracytoplasmic lipid droplets and mitochondria. This effect was accompanied by a significant and dose-dependent increase in intracellular triglyceride content (half-maximally effective dose 10−9M) and involved MR, because it was unaffected by RU-38486 treatment but was totally abolished in the presence of aldosterone antagonists (spironolactone, RU-26752). The expression of early adipogenic gene markers, such as lipoprotein lipase, peroxisome proliferator-activated receptor-γ, and adipocyte-specific fatty acid binding protein 2, was enhanced by aldosterone, confirming activation of the differentiation process. We demonstrate that, in the T37i cell line, aldosterone participates in the very early induction of brown adipocyte differentiation. Our findings may have a broader biological significance and suggest that MR is not only implicated in maintaining electrolyte homeostasis but could also play a role in metabolism and energy balance.
Short-term fasting abolishes the sex-related difference in GH and leptin secretion in humans
Authors: Maccario M. , Aimaretti G. , Corneli G. , Gauna C. , Grottoli S. , Bidlingmaier M. , Strasburger C. J. , Dieguez C. , Casanueva F. F. , Ghigo E.
Published: December 2017

We studied growth hormone (GH) and leptin secretion in eight male (age 29.3 ± 1.2 yr, body mass index 22.2 ± 0.5 kg/m2) and seven female normal subjects (28.0 ± 0.8 yr, 20.1 ± 0.7 kg/m2) before and after 36 h of fasting. In the fed state, 8-h mean GH and leptin concentrations were higher in females ( P < 0.05 and P < 0.0001, respectively). Fasting increased GH and decreased leptin in both sexes. There was significant interaction between gender and fasting ( P < 0.05 for GH and P < 0.005 for leptin). Females showed a slighter increase in GH but a more marked decrease in leptin, so that there was no significant gender-related difference in GH and leptin after fasting. Fasting did not modify insulin-like growth factor (IGF) I, IGF binding protein (IGFBP)-3, acid-labile subunit, or GH binding protein; increased IGFBP-1 and free fatty acids ( P < 0.0001) but decreased glucose ( P< 0.001) and insulin levels ( P < 0.05). In males, insulin levels were higher ( P < 0.05) in the fed state and underwent deeper reduction after fasting (interaction P < 0.03). In conclusion, GH and leptin secretions are higher in women than in men in the fed but not in the fasting condition, which abolishes these gender-related differences in humans.
Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle
Authors: Ellis Bronwyn A. , Poynten Ann , Lowy Andrew J. , Furler Stuart M. , Chisholm Donald J. , Kraegen Edward W. , Cooney Gregory J.
Published: December 2017

Long-chain acyl-CoAs (LCACoA) are an activated lipid species that are key metabolites in lipid metabolism; they also have a role in the regulation of other cellular processes. However, few studies have linked LCACoA content in rat and human muscle to changes in nutritional status and insulin action. Fasting rats for 18 h significantly elevated the three major LCACoA species in muscle ( P < 0.001), whereas high-fat feeding of rats with a safflower oil (18:2) diet produced insulin resistance and increased total LCACoA content ( P < 0.0001) by specifically increasing 18:2-CoA. The LCACoA content of red muscle from rats (4–8 nmol/g) was 4- to 10-fold higher than adipose tissue (0.4–0.9 nmol/g, P < 0.001), suggesting that any contamination of muscle samples with adipocytes would contribute little to the LCACoA content of muscle. In humans, the LCACoA content of muscle correlated significantly with a measure of whole body insulin action in 17 male subjects ( r2= 0.34, P = 0.01), supporting a link between muscle lipid metabolism and insulin action. These results demonstrate that the LCACoA pool reflects lipid metabolism and nutritional state in muscle. We conclude that the LCACoA content of muscle provides a direct index of intracellular lipid metabolism and its links to insulin action, which, unlike triglyceride content, is not subject to contamination by closely associated adipose tissue.
Adipocyte membrane phospholipids and PPAR-γ expression in obese women: relationship to hyperinsulinemia
Authors: Zeghari Nezha , Vidal Hubert , Younsi Mohamed , Ziegler Olivier , Drouin Pierre , Donner Mireille
Published: December 2017

We have shown that membrane sphingomyelin (SM) is an independent predictor of the variance of fasting plasma insulin (FPI) concentrations and the homeostasis model assessment (HOMA) estimate of insulin resistance in obese women. The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a key component in adipocyte differentiation that may also contribute to the sensitivity of cells to insulin. PPAR-γ is activated by fatty acids, and the membrane composition may have an impact on the activity of PPAR-γ and thus on the sensitivity of adipocytes to insulin. We investigated these possible links by determining the phospholipid contents of adipocyte membranes, the mRNA expression of PPAR-γ, and the FPI and HOMA estimate of insulin resistance in obese women. The mRNA levels of tumor necrosis factor-α (TNF-α), which is suspected to play a role in insulin resistance and which downregulates PPAR-γ expression, were also quantified. FPI and HOMA were strongly positively correlated with membrane SM ( P < 0.005) and cholesterol ( P < 0.005). PPAR-γ mRNA levels were negatively correlated with FPI ( P < 0.05) and HOMA ( P< 0.05) and positively correlated with high-density lipoprotein (HDL) cholesterol ( P < 0.05), membrane SM ( P < 0.05), and cholesterol contents ( P < 0.05). TNF-α mRNA levels were not correlated with membrane parameters. In stepwise multiple regression analysis, the variations in PPAR-γ mRNA levels were mainly explained by HDL cholesterol (31.9%) and membrane SM (17.7%). Our study shows that the expression of PPAR-γ, a major factor controlling adipocyte functions, the lipid composition of the membrane, and insulin sensitivity are probably closely associated in the adipose tissue of obese women.
Fatty acid profile of skeletal muscle phospholipids in trained and untrained young men
Authors: Andersson Agneta , Sjödin Anders , Hedman Anu , Olsson Roger , Vessby Bengt
Published: December 2017

Endurance trained ( n = 14) and untrained young men ( n = 15) were compared regarding the fatty acid profile of the vastus lateralis muscle after 8 wk on diets with a similar fatty acid composition. The skeletal muscle phospholipids in the trained group contained lower proportions of palmitic acid (16:0) (−12.4%, P < 0.001) and di-homo-γ-linolenic acid [20:3(n-6)] (−15.3%, P = 0.018), a lower n-6-to-n-3 ratio (−42.0%, P = 0.015), higher proportions of stearic acid (18:0) (+9.8%, P = 0.004) and sum of n-3 polyunsaturated fatty acids (+33.8%, P = 0.009), and a higher ratio between 20:4(n-6) to 20:3(n-6) (+18.4%, P = 0.006) compared with those in the untrained group. The group differences in 16:0, 20:3(n-6), 18:0/16:0, and 20:4(n-6)/20:3(n-6) were independent of fiber-type distribution. The trained group also showed a lower proportion of 16:0 (−7.9%, P < 0.001) in skeletal muscle triglycerides irrespective of fiber type. In conclusion, the fatty acid profile of the skeletal muscle differed between trained and untrained individuals, although the dietary fatty acid composition was similar. This difference was not explained by different fiber-type distribution alone but appears to be a direct consequence of changes in fatty acid metabolism due to the higher level of physical activity.
Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia
Authors: Parolin Michelle L. , Spriet Lawrence L. , Hultman Eric , Matsos Mark P. , Hollidge-Horvat Melanie G. , Jones Norman L. , Heigenhauser George J. F.
Published: December 2017

During the onset of exercise in hypoxia, the increased lactate accumulation is associated with a delayed activation of pyruvate dehydrogenase (PDH; Parolin ML, Spreit LL, Hultman E, Hollidge-Horvat MG, Jones NL, and Heigenhauser GJF. Am J Physiol Endocrinol Metab 278: E522–E534, 2000). The present study investigated whether activation of PDH with dichloroacetate (DCA) before exercise would reduce lactate accumulation during exercise in acute hypoxia by increasing oxidative phosphorylation. Six subjects cycled on two occasions for 15 min at 55% of their normoxic maximal oxygen uptake after a saline (control) or DCA infusion while breathing 11% O2. Muscle biopsies of the vastus lateralis were taken at rest and after 1 and 15 min of exercise. DCA increased PDH activity at rest and at 1 min of exercise, resulting in increased acetyl-CoA concentration and acetylcarnitine concentration at rest and at 1 min. In the first minute of exercise, there was a trend toward a lower phosphocreatine (PCr) breakdown with DCA compared with control. Glycogenolysis was lower with DCA, resulting in reduced lactate concentration ([lactate]), despite similar phosphorylase a mole fractions and posttransformational regulators. During the subsequent 14 min of exercise, PDH activity was similar, whereas PCr breakdown and muscle [lactate] were reduced with DCA. Glycogenolysis was lower with DCA, despite similar mole fractions of phosphorylase a, and was due to reduced posttransformational regulators. The results from the present study support the hypothesis that lactate production is due in part to metabolic inertia and cannot solely be explained by an oxygen limitation, even under conditions of acute hypoxia.
Effect of stimulation frequency on contraction-induced glucose transport in rat skeletal muscle
Authors: Ihlemann Jacob , Ploug Thorkil , Hellsten Ylva , Galbo Henrik
Published: December 2017

Previous studies have indicated that frequency of stimulation is a major determinant of glucose transport in contracting muscle. We have now studied whether this is so also when total force development or metabolic rate is kept constant. Incubated soleus muscles were electrically stimulated to perform repeated tetanic contractions at four different frequencies (0.25, 0.5, 1, and 2 Hz) for 10 min. Resting length was adjusted to achieve identical total force development or metabolic rate (glycogen depletion and lactate accumulation). Overall, at constant total force development, glucose transport (2-deoxyglucose uptake) increased with stimulation frequency ( P < 0.05; basal: 25 ± 2, 0.25 Hz: 50 ± 4, 0.5 Hz: 50 ± 3, 1 Hz: 81 ± 5, 2 Hz: 79 ± 3 nmol · g−1· 5 min−1). However, glucose transport was identical ( P > 0.05) at the two lower (0.25 and 0.5 Hz) as well as at the two higher (1 and 2 Hz) frequencies. Glycogen decreased ( P < 0.05; basal: 19 ± 1, 0.25 Hz: 13 ± 1, 0.5 Hz: 12 ± 2, 1 Hz: 7 ± 1, 2 Hz: 7 ± 1 mmol/kg) and 5′-AMP-activated protein kinase (AMPK) activity increased ( P < 0.05; basal: 1.7 ± 0.4, 0.25 Hz: 32.4 ± 7.0, 0.5 Hz: 36.5 ± 2.1, 1 Hz: 63.4 ± 8.0, 2 Hz: 67.0 ± 13.4 pmol · mg−1· min−1) when glucose transport increased. Experiments with constant metabolic rate were carried out in soleus, flexor digitorum brevis, and epitrochlearis muscles. In all muscles, glucose transport was identical at 0.5 and 2 Hz ( P > 0.05); also, AMPK activity did not increase with stimulation frequency. In conclusion, muscle glucose transport increases with stimulation frequency but only in the face of energy depletion and increase in AMPK activity. This indicates that contraction-induced glucose transport is elicited by metabolic demands rather than by events occurring early during the excitation-contraction coupling.
Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds
Authors: Davis Stephen N. , Shavers Chris , Costa Fernando
Published: December 2017

The aims of this study were 1) to determine whether differential glycemic thresholds are the mechanism responsible for the sexual dimorphism present in neuroendocrine responses during hypoglycemia and 2) to define the differences in counterregulatory physiological responses that occur over a range of mild to moderate hypoglycemia in healthy men and women. Fifteen (8 male, 7 female) lean healthy adults underwent four separate randomized 2-h hyperinsulinemic (1.5 mU · kg−1· min−1) glucose clamp studies at euglycemia (90 mg/dl) or hypoglycemia of 70, 60, or 50 mg/dl. Plasma insulin levels were similar during euglycemic and hypoglycemic studies (91–96 ± 8 μU/ml) in men and women. Hypoglycemia of 70, 60, and 50 mg/dl all resulted in significant increases ( P < 0.05, P < 0.01) in epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels compared with euglycemic studies in men and women. Plasma norepinephrine levels were increased ( P < 0.05) only relative to euglycemic studies at a hypoglycemia of 50 mg/dl. Muscle sympathetic nerve activity (MSNA) increased significantly during hyperinsulinemic-euglycemic control studies. Further elevations of MSNA did not occur until hypoglycemia of 60 mg/dl in both men and women. Plasma epinephrine, glucagon, growth hormone, and pancreatic polypeptide were significantly increased in men compared with women during hypoglycemia of 70, 60, and 50 mg/dl. MSNA, heart rate, and systolic blood pressure responses were also significantly increased in men at hypoglycemia of 60 and 50 mg/dl. In summary, these studies have demonstrated that, in healthy men and women, the glycemic thresholds for activation of epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide occur between 70 and 79 mg/dl. Thresholds for activation of MSNA occur between 60 and 69 mg/dl, whereas norepinephrine is not activated until glycemia is between 50 and 59 mg/dl. We conclude that 1) differential glycemic thresholds are not the cause of the sexual dimorphism present in counterregulatory responses to hypoglycemia; 2) reduced central nervous system efferent input appears to be the mechanism responsible for lowered neuroendocrine responses to hypoglycemia in women; and 3) physiological counterregulatory responses (neuroendocrine, cardiovascular, and autonomic nervous system) are reduced across a broad range of hypoglycemia in healthy women compared with healthy men.
Fatty acid transport protein-1 mRNA expression in skeletal muscle and in adipose tissue in humans
Authors: Binnert Christophe , Koistinen Heikki A. , Martin Geneviève , Andreelli Fabrizio , Ebeling Pertti , Koivisto Veikko A. , Laville Martine , Auwerx Johan , Vidal Hubert
Published: December 2017

Fatty acid transporter protein (FATP)-1 mRNA expression was investigated in skeletal muscle and in subcutaneous abdominal adipose tissue of 17 healthy lean, 13 nondiabetic obese, and 16 obese type 2 diabetic subjects. In muscle, FATP-1 mRNA levels were higher in lean women than in lean men (2.2 ± 0.1 vs. 0.6 ± 0.2 amol/μg total RNA, P < 0.01). FATP-1 mRNA expression was decreased in skeletal muscle in obese women both in nondiabetic and in type 2 diabetic patients ( P < 0.02 vs. lean women in both groups), and in all women there was a negative correlation with basal FATP-1 mRNA level and body mass index ( r = −0.74, P < 0.02). In men, FATP-1 mRNA was expressed at similar levels in the three groups both in skeletal muscle (0.6 ± 0.2, 0.6 ± 0.2, and 0.8 ± 0.2 amol/μg total RNA in lean, obese, and type 2 diabetic male subjects) and in adipose tissue (0.9 ± 0.2 amol/μg total RNA in the 3 groups). Insulin infusion (3 h) reduced FATP-1 mRNA levels in muscle in lean women but not in lean men. Insulin did not affect FATP-1 mRNA expression in skeletal muscle in obese nondiabetic or in type 2 diabetic subjects nor in subcutaneous adipose tissue in any of the three groups. These data show a gender-related difference in the expression of the fatty acid transporter FATP-1 in skeletal muscle of lean individuals and suggest that changes in FATP-1 expression may not contribute to a large extent to the alterations in fatty acid uptake in obesity and/or type 2 diabetes.
Age-induced changes in pancreatic islet blood flow: evidence for an impaired regulation in diabetic GK rats
Authors: Svensson Annika M. , Östenson Claes-Göran , Jansson Leif
Published: December 2017

The present study aimed to compare longitudinal variations in islet blood perfusion in rats with different degrees of impairment of glucose metabolism. For this purpose, mildly diabetic Goto-Kakizaki (GK) rats, glucose intolerant F1hybrids of GK and Wistar (W) rats (H), and control W rats were examined at 5 wk, 12 wk, or 1 yr of age, using the microsphere technique for blood flow measurements. W rats showed progressively increasing islet blood flow (IBF) throughout the experiment. Both GK and H rats demonstrated increasing IBF between 5 and 12 wk. However, H rats showed no further increment in IBF at 1 yr, whereas GK rats displayed a pronounced decrease in IBF between 12 wk and 1 yr of age. The augmented IBF seen in older W rats may constitute an adaptation to the increasing demand for insulin secretion in aging rats. The inability to adapt to the increased demand for insulin secretion by upregulation of islet blood flow could contribute to the progressive deterioration of glucose metabolism seen in the aging GK rat.
Acute reversal of lipid-induced muscle insulin resistance is associated with rapid alteration in PKC-θ localization
Authors: Bell Kim S. , Schmitz-Peiffer Carsten , Lim-Fraser Megan , Biden Trevor J. , Cooney Gregory J. , Kraegen Edward W.
Published: December 2017

Muscle insulin resistance in the chronic high-fat-fed rat is associated with increased membrane translocation and activation of the novel, lipid-responsive, protein kinase C (nPKC) isozymes PKC-θ and -ɛ. Surprisingly, fat-induced insulin resistance can be readily reversed by one high-glucose low-fat meal, but the underlying mechanism is unclear. Here, we have used this model to determine whether changes in the translocation of PKC-θ and -ɛ are associated with the acute reversal of insulin resistance. We measured cytosol and particulate PKC-α and nPKC-θ and -ɛ in muscle in control chow-fed Wistar rats (C) and 3-wk high-fat-fed rats with (HF-G) or without (HF-F) a single high-glucose meal. PKC-θ and -ɛ were translocated to the membrane in muscle of insulin-resistant HF-F rats. However, only membrane PKC-θ was reduced to the level of chow-fed controls when insulin resistance was reversed in HF-G rats [% PKC-θ at membrane, 23.0 ± 4.4% (C); 39.7 ± 3.4% (HF-F, P < 0.01 vs. C); 22.5 ± 2.7% (HF-G, P < 0.01 vs. HF-F), by ANOVA]. We conclude that, although muscle localization of both PKC-ɛ and PKC-θ are influenced by chronic dietary lipid oversupply, PKC-ɛ and PKC-θ localization are differentially influenced by acute withdrawal of dietary lipid. These results provide further support for an association between PKC-θ muscle cellular localization and lipid-induced muscle insulin resistance and stress the labile nature of high-fat diet-induced insulin resistance in the rat.
Norepinephrine-induced sustained inward current in brown fat cells: α1-mediated by nonselective cation channels
Authors: Koivisto Ari , Siemen Detlef , Nedergaard Jan
Published: December 2017

The nature of the sustained norepinephrine-induced depolarization in brown fat cells was examined by patch-clamp techniques. Norepinephrine (NE) stimulation led to a whole cell current response consisting of two phases: a first inward current, lasting for only 1 min, and a sustained inward current, lasting as long as the adrenergic stimulation was maintained. The nature of the sustained current was here investigated. It could be induced by the α1-agonist cirazoline but not by the β3-agonist CGP-12177A. Reduction of extracellular Cl−concentration had no effect, but omission of extracellular Ca2+or Na+totally eliminated it. When unstimulated cells were studied in the cell-attached mode, some activity of ≈30 pS nonselective cation channels was observed. NE perfusion led to a 10-fold increase in their open probability (from ≈0.002 to ≈0.017), which persisted as long as the perfusion was maintained. The activation was much stronger with the α1-agonist phenylephrine than with the β3-agonist CGP-12177A, and with the Ca2+ionophore A-23187 than with the adenylyl cyclase activator forskolin. We conclude that the sustained inward current was due to activation of ≈30 pS nonselective cation channels via α1-adrenergic receptors and that the effect may be mediated via an increase in intracellular free Ca2+concentration.
Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation
Authors: Benthem Lambertus , Keizer Klaasjan , Wiegman Coen H. , de Boer Sietse F. , Strubbe Jan H. , Steffens Anton B. , Kuipers Folkert , Scheurink Anton J. W.
Published: December 2017

We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the long-chain fatty acid oleate (150 nmol/min, 24 h), the medium-chain fatty acid caprylate, or the solvent. Corticosterone (Cort) and norepinephrine (NE) were measured as indexes for HPA axis and sympathetic activity, respectively. Insulin sensitivity was assessed by means of an intravenous glucose tolerance test (IVGTT). Oleate infusion induced increases in plasma Cort (Δ = 13.5 ± 3.6 μg/dl; P < 0.05) and NE (Δ = 235 ± 76 ng/l; P < 0.05), whereas caprylate and solvent had no effect. The area under the insulin response curve to the IVGTT was larger in the oleate-treated group than in the caprylate and solvent groups (area = 220 ± 35 vs. 112 ± 13 and 106 ± 8, respectively, P < 0.05). The area under the glucose response curves was comparable [area = 121 ± 13 (oleate) vs. 135 ± 20 (caprylate) and 96 ± 11 (solvent)]. The results are consistent with the concept that increased portal free fatty acid is involved in the induction of visceral obesity-related insulin resistance via activation of the HPA axis and sympathetic system.
Androgen regulation and site specificity of angiotensinogen gene expression and secretion in rat adipocytes
Authors: Serazin-Leroy Valérie , Morot Mireille , de Mazancourt Philippe , Giudicelli Yves
Published: December 2017

Adipose tissue is an important source of angiotensinogen (ATG), and hypertension is commonly associated with android obesity. Therefore, we tested the hypothesis that androgens may control ATG gene expression and secretion in rat fat cells. In intact male rats, ATG mRNA expression (Northern blot and co-reverse transcription-polymerase chain reaction analysis) and protein secretion were significantly higher in deep intra-abdominal (perirenal and epididymal) than in subcutaneous adipocytes. After castration, ATG mRNA was reduced almost 50% in the three fat deposits, with parallel changes in ATG protein secretion. Conversely, testosterone treatment fully restored the ATG mRNA decrease after castration, whatever the anatomical origin of the adipocytes. Finally, a 24-h in vitro exposure of perirenal fat cells or differentiated preadipocytes from castrated rats to testosterone or dihydrotestosterone (10 nM free hormone concentration) increased ATG mRNA expression by 50–100%, an effect that was prevented by the anti-androgen cyproterone acetate. These data, demonstrating both in vivo and in vitro androgen induction of ATG mRNA expression in rat adipocytes, add further weight to the hypothesis of a link between adipose tissue ATG production, androgens, and android obesity-related hypertension.
Effect of hypothyroidism on pathways for iodothyronine and tryptophan uptake into rat adipocytes
Authors: Ritchie James W. A. , Collingwood Charmian J. F. , Taylor Peter M.
Published: December 2017

Adipocytes are an important target tissue for thyroid hormone action, but little is known of the mechanisms of thyroid hormone entry into the cells. The present results show a strong interaction between transport of iodothyronines [l-thyroxine (T4),l-triiodothyronine (T3), reverset3(rT3)], aromatic amino acids, and the System L amino acid transport inhibitor 2-amino[2,2,1]heptane-2-carboxylic acid (BCH) in white adipocytes. System L appears to be a major pathway of iodothyronine and large neutral amino acid entry into these cells in the euthyroid state. We also demonstrate expression of the CD98hc peptide subunit of the System L transporter in adipocyte cell membranes. Experimental hypothyroidism (28-day propylthiouracil treatment) has no significant effect on Systeml-like transport of the amino acid tryptophan in adipocytes. In contrast, uptake of T3and especially T4is substantially reduced in adipocytes from hypothyroid rats, partly due to reduction of the BCH-sensitive transport component. Transport of iodothyronines and amino acids in adipocytes therefore becomes decoupled in the hypothyroid state, as occurs similarly in liver cells. This may be due to downregulation or dissociation of iodothyronine receptors from the System L transporter complex. Regulation of iodothyronine turnover in fat cells by this type of mechanism could contribute significantly to modulation of T4-T3/rT3metabolism in the hypothyroid state.
Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids
Authors: Young Martin E. , Goodwin Gary W. , Ying Jun , Guthrie Patrick , Wilson Christopher R. , Laws Frank A. , Taegtmeyer Heinrich
Published: December 2017

Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-α (PPARα). Specific PPARα stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARγ agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARα expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.
[5-3H]glucose overestimates glycolytic flux in isolated working rat heart: role of the pentose phosphate pathway
Authors: Goodwin Gary W. , Cohen David M. , Taegtmeyer Heinrich
Published: December 2017

We set out to study the pentose phosphate pathway (PPP) in isolated rat hearts perfused with [5-3H]glucose and [1-14C]glucose or [6-14C]glucose (crossover study with 1- then 6- or 6- then 1-14C-labeled glucose). To model a physiological state, hearts were perfused under working conditions with Krebs-Henseleit buffer containing 5 mM glucose, 40 μU/ml insulin, 0.5 mM lactate, 0.05 mM pyruvate, and 0.4 mM oleate/3% albumin. The steady-state C1/C6 ratio (i.e., the ratio from [1-14C]glucose to [6-14C]glucose) of metabolites released by the heart, an index of oxidative PPP, was not different from 1 (1.06 ± 0.19 for14CO2, and 1.00 ± 0.01 for [14C]lactate + [14C]pyruvate, mean ± SE, n = 8). Hearts exhibited contractile, metabolic, and14C-isotopic steady state for glucose oxidation (14CO2production). Net glycolytic flux (net release of lactate + pyruvate) and efflux of [14C]lactate + [14C]pyruvate were the same and also exhibited steady state. In contrast, flux based on3H2O production from [5-3H]glucose increased progressively, reaching 260% of the other measures of glycolysis after 30 min. The3H/14C ratio of glycogen (relative to extracellular glucose) and sugar phosphates (representing the glycogen precursor pool of hexose phosphates) was not different from each other and was <1 (0.36 ± 0.01 and 0.43 ± 0.05 respectively, n = 8, P < 0.05 vs. 1). We conclude that both transaldolase and the L-type PPP permit hexose detritiation in the absence of net glycolytic flux by allowing interconversion of glycolytic hexose and triose phosphates. Thus apparent glycolytic flux obtained by3H2O production from [5-3H]glucose overestimates the true glycolytic flux in rat heart.
Effect of nicotinic acid administration on hepatic very low density lipoprotein-triglyceride production
Authors: Wang Wei , Basinger Alice , Neese Richard A. , Shane Barry , Myong Su-A , Christiansen Mark , Hellerstein Marc K.
Published: December 2017

Our objective was to examine very low density lipoprotein-triglyceride (VLDL-TG) kinetics after chronic and acute administration of nicotinic acid (NA). Incorporation of [1,2,3,4-13C4]palmitate and [2-13C1]glycerol into VLDL-TG was measured in five healthy, normolipidemic women. Each subject was studied twice; the 4-day hospital stays were separated by 1 mo, during which time doses of NA were increased to 2 g/day (500 mg, 4 times/day). During posttreatment study, 500 mg of NA were administered acutely at 0800. Under baseline postabsorptive conditions, incorporation curves from13C-labeled free fatty acid (FFA) and13C-labeled glycerol were superimposable, and VLDL-TG kinetics were in agreement ( t1/2= 1.4 ± 0.3 and 1.3 ± 0.3 h, and production rates = 27.2 ± 6.1 and 28.5 ± 5.3 g/day, respectively). In the postabsorptive state after chronic NA therapy, VLDL-TG concentrations and production rates were lower despite a trend toward elevated plasma FFA concentrations and fluxes. After the acute dose of NA, plasma FFA concentrations and flux fell dramatically, and there was a virtual halt to VLDL-TG production, which continued throughout the 6-h period after NA, despite a marked rebound overshoot in serum FFA concentrations and flux after hour 2. Plasma homocysteine concentrations increased 68% ( P < 0.001) in the NA phase, consistent with chronic increased transmethylation demand. We conclude that 1) NA acutely and chronically decreases VLDL-TG production rate in normal women; 2) the acute effect on VLDL-TG production is associated with an initial suppression of lipolysis but persists for several hours after the antilipolytic action of NA has abated and is observed in the basal postabsorptive state, when lipolytic rates are not reduced; and 3) the effect of NA on VLDL-TG production, therefore, cannot be completely explained by its antilipolytic actions.
Effects of clenbuterol on insulin resistance in conscious obese Zucker rats
Authors: Pan Shujia J. , Hancock Joe , Ding Zhenping , Fogt Donovan , Lee Mancheong , Ivy John L.
Published: December 2017

The present study was conducted to determine the effect of chronic administration of the long-acting β2-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats ( fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin · kg−1· min−1) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.
Preoperative oral carbohydrate treatment attenuates immediate postoperative insulin resistance
Authors: Soop Mattias , Nygren Jonas , Myrenfors Peter , Thorell Anders , Ljungqvist Olle
Published: December 2017

Postoperative insulin resistance is a well-characterized metabolic state that has been shown to correlate with the length of postoperative stay in hospital. Preoperative intravenous or oral carbohydrate treatment has been shown to attenuate the development of postoperative insulin resistance measured 1 day after surgery. To study the effects of preoperative oral carbohydrate treatment on postoperative changes in insulin resistance and substrate utilization, in the absence of postoperative confounding factors, 15 patients were double-blindly treated with either a carbohydrate-rich beverage (12.5%) ( n = 8) or placebo ( n = 7) before undergoing total hip replacement surgery. Insulin sensitivity, endogenous glucose release, and substrate oxidation rates were measured before and immediately after surgery. Whole body insulin sensitivity decreased by 18% in the treatment group vs. 43% in the placebo group ( P < 0.05, Student's t-test for unpaired data). In both groups, the major mechanism of insulin resistance was an inhibition of insulin-induced nonoxidative glucose disposal after surgery. The better preservation of insulin sensitivity in the treatment group was attributable to a less reduced glucose disposal in peripheral tissues and increased glucose oxidation rates.
A high-sucrose diet increases gluconeogenic capacity in isolated periportal and perivenous rat hepatocytes
Authors: Bizeau Michael E. , Thresher Jeffrey S. , Pagliassotti Michael J.
Published: December 2017

A high-sucrose (SU) diet increases gluconeogenesis (GNG) in the liver. The present study was conducted to determine the contribution of periportal (PP) and perivenous (PV) cell populations to this SU-induced increase in GNG. Male Sprague-Dawley rats were fed an SU (68% sucrose) or starch (ST, 68% starch) diet for 1 wk, and hepatocytes were isolated from the PP or PV region of the liver acinus. Hepatocytes were incubated for 1 h in the presence of various gluconeogenic substrates, and glucose release into the medium was used to estimate GNG. When incubated in the presence of 5 mM lactate, which enters GNG at the level of pyruvate, glucose release (nmol · h−1· mg−1) was significantly increased by the SU diet in both PP (84.8 ± 3.4 vs. 70.4 ± 2.6) and PV (64.3 ± 2.5 vs. 38.2 ± 2.1) cells. Addition of palmitate (0.5 mM) increased glucose release from lactate in PP cells by 11.6 ± 0.5 and 20.6 ± 1.5% and in PV cells by 11.0 ± 4.4 and 51.1 ± 9.1% in SU and ST, respectively. When cells were incubated with 5 mM dihydroxyacetone (DHA), which enters GNG at the triosephosphate level, glucose release was significantly increased by the SU diet in both cell types. In contrast, glucose release from fructose (0.5 mM) was significantly increased by the SU diet in PV cells only. These changes in glucose release were accompanied by significant increases in the maximal specific activities of glucose-6-phosphatase (G-6-Pase) and phospho enolpyruvate carboxykinase (PEPCK) in both PP and PV cells. These data suggest that the SU diet influences GNG in both PP and PV cell populations. It appears that SU feeding produces changes in GNG via alterations in at least two critical enzymes, G-6-Pase and PEPCK.
Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects
Authors: Liu Li , Li Antai , Matthews Stephen G.
Published: December 2017

Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on days 40–41, days 50–51, and days 60–61 of gestation. Adult offspring were split into two groups. Group 1 guinea pigs were catheterized, and the hypothalamo-pituitary-adrenal (HPA) axis was tested in basal and activated states. Group 2 guinea pigs were euthanized with no further manipulation. In male offspring, prenatal dexamethasone exposure resulted in a significant reduction in brain-to-body weight ratio. Dexamethasone-exposed male offspring exhibited reduced basal and activated plasma cortisol levels, which was associated with elevated hippocampal mineralocorticoid receptor (MR) mRNA and increased plasma testosterone. In females exposed to glucocorticoids in utero, basal and stimulated plasma cortisol levels were higher in the follicular and early luteal phases of the cycle, but this effect was reversed in the late luteal phase, indicating a significant interaction of sex steroids. In female offspring (at estrus), glucocorticoid receptor mRNA levels were lower in the paraventricular nucleus and pars distalis but higher in the hippocampus in animals exposed to dexamethasone in utero. Hippocampal MR mRNA levels were significantly lower (∼50%) than in controls. In conclusion, repeated antenatal glucocorticoid treatment programs HPA function in a sex-specific manner, and these changes are associated with modification of corticosteroid receptor expression in the adult brain and pituitary.
Effects of β-adrenergic receptor stimulation and blockade on substrate metabolism during submaximal exercise
Authors: Mora-Rodriguez Ricardo , Hodgkinson Bradley J. , Byerley Lauri O. , Coyle Edward F.
Published: December 2017

We used β-adrenergic receptor stimulation and blockade as a tool to study substrate metabolism during exercise. Eight moderately trained subjects cycled for 60 min at 45% of V˙o2 peak1) during a control trial (CON); 2) while epinephrine was intravenously infused at 0.015 μg · kg−1· min−1(β-STIM); 3) after ingesting 80 mg of propranolol (β-BLOCK); and 4) combining β-BLOCK with intravenous infusion of Intralipid-heparin to restore plasma fatty acid (FFA) levels (β-BLOCK+LIPID). β-BLOCK suppressed lipolysis (i.e., glycerol rate of appearance) and fat oxidation while elevating carbohydrate oxidation above CON (135 ± 11 vs. 113 ± 10 μmol · kg−1· min−1; P < 0.05) primarily by increasing rate of disappearance (Rd) of glucose (36 ± 2 vs. 22 ± 2 μmol · kg−1· min−1; P < 0.05). Plasma FFA restoration (β-BLOCK+LIPID) attenuated the increase in Rdglucose by more than one-half (28 ± 3 μmol · kg−1· min−1; P < 0.05), suggesting that part of the compensatory increase in muscle glucose uptake is due to reduced energy from fatty acids. On the other hand, β-STIM markedly increased glycogen oxidation and reduced glucose clearance and fat oxidation despite elevating plasma FFA. Therefore, reduced plasma FFA availability with β-BLOCK increased Rdglucose, whereas β-STIM increased glycogen oxidation, which reduced fat oxidation and glucose clearance. In summary, compared with control exercise at 45%V˙o2 peak(CON), both β-BLOCK and β-STIM reduced fat and increased carbohydrate oxidation, albeit through different mechanisms.
Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle
Authors: Oku Akira , Nawano Masao , Ueta Kiichiro , Fujita Takuya , Umebayashi Itsuro , Arakawa Kenji , Kano-Ishihara Tomomi , Saito Akira , Anai Motonobu , Funaki Makoto , Kikuchi Masayoshi , Oka Yoshitomo , Asano Tomoichiro
Published: December 2017

To determine the molecular mechanism underlying hyperglycemia-induced insulin resistance in skeletal muscles, postreceptor insulin-signaling events were assessed in skeletal muscles of neonatally streptozotocin-treated diabetic rats. In isolated soleus muscle of the diabetic rats, insulin-stimulated 2-deoxyglucose uptake, glucose oxidation, and lactate release were all significantly decreased compared with normal rats. Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. The amelioration of hyperglycemia by T-1095, a Na+-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle.
The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation
Authors: Frühbeck Gema , Gómez-Ambrosi Javier , Muruzábal Francisco José , Burrell María Angela
Published: December 2017

The ability to ensure continous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-α, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess.
Nicotine infusion alters leptin and uncoupling protein 1 mRNA expression in adipose tissues of rats
Authors: Arai Keiko , Kim Kyongsong , Kaneko Katsumi , Iketani Mitsue , Otagiri Asuka , Yamauchi Naoko , Shibasaki Tamotsu
Published: December 2017

We attempted to clarify whether leptin and uncoupling protein 1 (UCP1) are involved in the action of nicotine on the energy balance. Male Wistar rats were infused subcutaneously with nicotine (12 mg · kg−1 · day−1) for 4 or 14 days. At the end of the 4-day period, the plasma concentrations of leptin of the nicotine-treated and pair-fed rats were lower than those of the freely fed rats, although the levels of leptin mRNA expression in various white adipose tissues did not differ among the three groups. At the end of the 14-day nicotine infusion period, plasma concentrations of leptin were higher, and leptin mRNA expression in the omentum and epididymal and retroperitoneal adipose tissues was stronger in the nicotine-treated rats than in the pair-fed and freely fed rats. UCP1 mRNA expression in the brown adipose tissue of nicotine-treated was stronger than that of the pair-fed rats. These results suggest that continuous nicotine infusion differentially affects the synthesis and secretion of leptin according to the duration of infusion and stimulates UCP1 mRNA expression, probably in a manner independent of leptin.