Glucose Utilization In Adipose Tissue Research Articles

Transcriptomic Responses Induced in Muscle and Adipose Tissues of Growing Pigs by Intravenous Infusion of Sodium Butyrate.

Simple SummaryThe present study was constructed to determine the effects of short-term intravenous sodium butyrate (SB) administration on metabolism through transcriptomic responses in muscle and adipose tissue of pigs. We found that systemic butyrate displayed a discriminative metabolic regulation in muscle and adipose tissue. Intravenous SB infusion decreased amino acid metabolism pathways both in muscle and adipose tissues. Intravenous SB infusion increased glucose catabolism in muscle tissue and decreased glucose utilization in adipose tissue. Moreover, intravenous SB infusion decreased lipolysis in muscle tissue but increased lipolysis in adipose tissue. These findings support the direct role of the SCFA butyrate in the regulation of the metabolism.Butyrate has a central function in the regulation of energy metabolism as a metabolite of bacterial fermentation. This study evaluated the effects of intravenous sodium butyrate (SB) administration on the transcriptome of muscle and adipose tissue of pigs. Twelve crossbred barrows (Duroc × Landrace × Large White) were fitted with a medical polyethylene cannula via the internal jugular vein and were daily infused with 10 mL SB (200 mmol/L) or the same volume of physiological saline. Muscle transcriptome showed 11 DEGs related to carbohydrate metabolism, 28 DEGs related to lipid metabolism, and 10 DEGs related to amino acid metabolism. Among these, carbohydrate catabolic process-related genes (PPP1R3B, PRPS2, ALDOC), fatty acid synthase (FASN), and lipolysis-related genes (PLIN1) were upregulated, while the carbohydrate biosynthetic process-related genes (PCK1) and most amino acid metabolism-related genes were downregulated. Adipose transcriptome showed 12 DEGs related to carbohydrate metabolism, 27 DEGs related to lipid metabolism, and 10 DEGs related to amino acid metabolism. Among these, carbohydrate metabolism-related genes (IGF1, LEP, SLC2A4) and lipolysis-related genes (LPL) were upregulated, while lipolysis-related genes (ANGPTL4) and most amino acid metabolism-related genes were downregulated. The results suggest that short-term intravenous SB infusion could modulate the muscle and adipose tissue metabolism at the transcriptional level by decreasing amino acid metabolism pathways. Additionally, intravenous SB increased the glucose catabolism in muscle tissue and decreased the glucose utilization in adipose tissue. Intravenous SB increased the fatty acid synthesis, decreased the lipolysis in muscle tissue, and increased the lipolysis in adipose tissue. This suggests that systemic butyrate may display discriminative metabolic regulation in different tissues of barrows.

Adipose Tissue Plasticity During Catch-Up Fat Driven by Thrifty Metabolism

OBJECTIVECatch-up growth, a risk factor for later type 2 diabetes, is characterized by hyperinsulinemia, accelerated body-fat recovery (catch-up fat), and enhanced glucose utilization in adipose tissue. Our objective was to characterize the determinants of enhanced glucose utilization in adipose tissue during catch-up fat.RESEARCH DESIGN AND METHODSWhite adipose tissue morphometry, lipogenic capacity, fatty acid composition, insulin signaling, in vivo glucose homeostasis, and insulinemic response to glucose were assessed in a rat model of semistarvation-refeeding. This model is characterized by glucose redistribution from skeletal muscle to adipose tissue during catch-up fat that results solely from suppressed thermogenesis (i.e., without hyperphagia).RESULTSAdipose tissue recovery during the dynamic phase of catch-up fat is accompanied by increased adipocyte number with smaller diameter, increased expression of genes for adipogenesis and de novo lipogenesis, increased fatty acid synthase activity, increased proportion of saturated fatty acids in triglyceride (storage) fraction but not in phospholipid (membrane) fraction, and no impairment in insulin signaling. Furthermore, it is shown that hyperinsulinemia and enhanced adipose tissue de novo lipogenesis occur concomitantly and are very early events in catch-up fat.CONCLUSIONSThese findings suggest that increased adipose tissue insulin stimulation and consequential increase in intracellular glucose flux play an important role in initiating catch-up fat. Once activated, the machinery for lipogenesis and adipogenesis contribute to sustain an increased insulin-stimulated glucose flux toward fat storage. Such adipose tissue plasticity could play an active role in the thrifty metabolism that underlies glucose redistribution from skeletal muscle to adipose tissue.

Peroxisome Proliferator-Activated Receptor-α-Null Mice Have Increased White Adipose Tissue Glucose Utilization, GLUT4, and Fat Mass: Role in Liver and Brain

Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

Glucocorticoids are important hormones in the regulation of metabolic homeostasis. We infused normal rats with dexamethasone given intracerebroventricularly (i.c.v.) for 3 days. This resulted in hyperphagia, hyperinsulinemia, and marked insulin resistance. Similar metabolic defects were observed following i.c.v. infusion of neuropeptide Y (NPY) in normal rats. As central dexamethasone infusion enhanced NPY content in the arcuate nucleus, it suggested that its metabolic effects are mediated by NPY. Moreover, due to the lack of effects observed in vagotomized animals, activation of the parasympathetic nervous system by central dexamethasone infusion is proposed. Glucocorticoid action is known to involve prereceptor metabolism by enzymes such as 11beta-HSD-1 that converts inactive into active glucocorticoids. Mice overexpressing 11beta-HSD-1 in adipose tissue were shown to be obese and insulin resistant. We recently observed that adipose tissue 11beta-HSD-1 mRNA expression is increased at the onset of high-fat diet-induced obesity and positively correlated with the degree of hyperglycemia. In human obesity, increased adipose tissue 11beta-HSD-1 expression and activity were also reported. Resistin is a new adipose tissue-secreted hormone shown to play a role in glucose homeostasis by increasing hepatic glucose production and inhibiting muscle and adipose tissue glucose utilization. We observed increased adipose tissue resistin expression in the early phase of high-fat diet-induced obesity as well as decreased resistin expression in response to leptin. A positive correlation between glycemia and adipose tissue resistin expression further suggested a role of this hormone in the development of insulin resistance. The melanocortin system is another important player in the regulation of energy balance. Peripheral administration of a melanocortin agonist decreased food intake and body weight and favored lipid oxidation, effects that were more marked in obese than in lean rats. It is proposed that both resistin and melanocortin agonists may influence adipose tissue 11beta-HSD-1, thereby decreasing or enhancing glucose metabolism.

Increased insulin concentrations and glucose storage in neuropeptide Y Y1 receptor-deficient mice

Mice lacking NPY Y1 receptors develop obesity without hyperphagia indicating increased energy storage and/or decreased energy expenditure. Then, we investigated glucose utilization in these animals at the onset of obesity. Fasted NPY Y1 knockouts showed hyperinsulinemia associated with increased whole body and adipose tissue glucose utilization and glycogen synthesis but normal glycolysis. Since leptin modulates NPY actions, we studied whether the lack of NPY Y1 receptor affected leptin-mediated regulation of glucose metabolism. Leptin infusion normalized hyperinsulinemia and glucose turnover. These results suggest a possible mechanism for the development of obesity without hyperphagia via dysfunction in regulatory loops involving NPY, leptin and insulin.

Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins.

Continuous (4 days) intracerebroventricular leptin infusion (12 microg/day) was performed in lean rats, and its hormonometabolic effects were determined. Intracerebroventricular leptin administration did not result in leakage of the hormone into the peripheral circulation. Thus, its effects were elicited by its presence within the central nervous system. Intracerebroventricular leptin infusion produced marked decreases in food intake and body weight gain relative to vehicle-infused fed ad libitum rats. Because decreases in food intake alter hormonometabolic homeostasis, additional control rats pair-fed to the amount of food consumed by leptin-infused ones were included in the study. Intracerebroventricular leptin-infused and vehicle-infused pair-fed rats were characterized, relative to vehicle-infused ad libitum-fed animals, by decreases in body weight and insulinemia and by increases in insulin-stimulated overall glucose utilization and muscle and brown adipose tissue glucose utilization index. Brown adipose tissue uncoupling protein (UCP)1, UCP2, and UCP3 mRNA levels were markedly decreased in pair-fed animals relative to those of fed ad libitum control animals, as were liver and white adipose tissue UCP2 and muscle UCP3 mRNA levels. In marked contrast, intracerebroventricular leptin administration was accompanied by the maintenance of high UCP1, UCP2, and UCP3 expression in all these tissues. Thus, despite analogies between leptin's effects and those of pair-feeding with regard to glucose handling, their respective underlying mechanisms differ. While leptin maintains or favors energy-dissipating mechanisms (UCP1, UCP2, and UCP3), the latter are markedly depressed in pair-fed rats. This effect of leptin may prevent subsequent excessive storage processes, thereby maintaining normal body homeostasis.

Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat.

Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin-responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.

Adrenergic regulation of human adipose tissue metabolism in situ during mental stress.

The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in situ during a standardized mental stress test in 11 nonobese, healthy subjects, using microdialysis of the extracellular water space in sc adipose tissue. Microdialysis probes were inserted in the abdominal sc fat, and were perfused using solvents with or without adrenoceptor blocking agents. The tissue dialysate concentrations of glycerol (lipolysis index) glucose, lactate, and pyruvate were determined. The glycerol concentration in adipose tissue increased markedly during the stress test and decreased in the poststress period. A similar kinetic pattern was observed in blood. In situ administration of the nonselective beta-adrenoceptor blocking agent propranolol almost completely prevented the stress-induced increase in adipose tissue glycerol levels, whereas a nonselective alpha-adrenoceptor blocking agent (phentolamine) was ineffective in this respect. Plasma levels of glucose and lactate remained unaltered during and after the stress test; at the same time plasma pyruvate decreased moderately. By contrast, glucose, lactate, and pyruvate in adipose tissue increased by 25-30% during or after the stress (P < 0.05). The increase in lactate and pyruvate in adipose tissue after the stress was completely off-set by alpha-adrenoceptor blockade in situ, whereas beta-adrenoceptor blockade in situ did not influence the kinetic pattern of these metabolites. It is concluded that the lipolytic activity in human adipose tissue is markedly enhanced during mental stress, owing to adrenergic mechanisms that are mediated via beta-adrenoceptors. After mental stress, adipose tissue glucose utilization is decreased and routed toward nonoxidative pathways. The latter seems to involve adrenergic effects that are mediated via alpha-adrenoceptors.

Effect of insulin on human adipose tissue metabolism in situ. Interactions with beta-adrenoceptors.

The effects of insulin, and its interactions with catecholamines through beta-adrenoceptors, on human adipose tissue glucose utilization and lipolysis were investigated in vivo. Microdialysis of the extracellular compartment of abdominal subcutaneous adipose tissue was performed in healthy subjects of normal weight, before and during a 2-h hyperinsulinaemic (61 +/- 3 mU/l), euglycaemic clamp. The tissue was perfused with or without the beta-adrenergic agonist isoproterenol (10(-6) mol/l), and the tissue dialysate concentrations of glucose, glycerol (lipolysis index) lactate and pyruvate were determined. During the insulin infusion, glucose in adipose tissue decreased by 20% (p less than 0.001), despite arterial steady-state normoglycaemia. The concentrations of lactate and pyruvate increased gradually to a steady-state plateau of twice the basal level in adipose tissue and arterial blood. Insulin-induced suppression of glycerol (lipolysis index) was, if anything, more marked in adipose tissue than in plasma (65% vs 50% decrease from baseline levels, p less than 0.05). In situ perfusion of adipose tissue with isoproterenol, starting either at the beginning of the study period or at 45 min after initiation of the insulin infusion, resulted in marked and rapid elevations of all the investigated metabolites in the adipose tissue extracellular compartment (p less than 0.05-0.005). It is concluded that insulin action on glucose uptake and lipolysis in human adipose tissue in vivo is counteracted by beta-adrenoceptor stimulation. In contrast, insulin and beta-adrenoceptors have synergistic effects on non-oxidative glucose metabolism in human adipose tissue in situ.

Effect of Excess Dietary Fat during the Third Trimester of Pregnancy on Maternal, Placental, and Fetal Metabolism in the Pig

The effect of excessive intake of dietary fat during late gestation on maternal, placental, and fetal metabolism was studied. Twelve pregnant gilts were fed ad libitum diets containing 4 (control) or 55% (added fat) calories as fat, beginning on day 70 of gestation. On day 110, glucose and palmitate oxidation, and incorporation into fatty acids by maternal adipose tissue, maternal and fetal placenta, and fetal liver and adipose tissue were determined. Caloric efficiency and adipose tissue glucose utilization were reduced in the added fat gilts, while placenta metabolism at high media palmitate concentrations was increased. Fetal development and metabolism were for the most part unaffected by maternal diet; thus, the fetus appears to be protected from dietary excess through adaptations of both maternal and placental metabolism.

Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivo.

The pathophysiological significance of the glucose-fatty acid cycle in skeletal muscle in vivo is uncertain. We have examined the short term effects of increased availability of nonesterified FFA on tissue-specific glucose uptake and storage in rat tissues in vivo basally and during a hyperinsulinemic (150 mU/liter) euglycemic clamp. Circulating FFA were elevated to 2 mmol/liter (FFA 1) or 4 mmol/liter (FFA 2). Elevated FFA produced a dose-dependent inhibition of myocardial glucose utilization in both basal (FFA1, 42%; FFA2, 68%; P less than 0.001, by analysis of variance) and clamp groups (FFA1, 39%; FFA2, 49%; P less than 0.001) and also suppressed brown adipose tissue glucose utilization during the clamp (-42%, P less than 0.001). In contrast to heart, glucose utilization in skeletal muscle was suppressed by FFA only in the FFA1 basal group (-36%, P less than 0.001); in other groups (e.g., FFA2 clamp) elevated FFA produced increased skeletal muscle glucose utilization (+68%, P less than 0.001) that was directed toward glycogen (+175%, P less than 0.05) and lipid deposition (+125%, P less than 0.005). FFA stimulated basal glucose utilization in white (e.g., FFA2, +220%, P less than 0.005) and brown adipose tissue (e.g., FFA2, +200%, P less than 0.005). Thus elevated FFA can acutely inhibit glucose utilization in skeletal muscle in addition to cardiac muscle in vivo supporting a possible role for the glucose-fatty acid cycle in skeletal muscle in acute insulin resistance. However, at high levels or with elevated insulin, FFA stimulates glucose utilization and storage in skeletal muscle. By promoting accumulation of glucose storage products, chronic elevation of FFA may lead to skeletal muscle (and therefore whole body) insulin resistance.

Interactions of insulin and dexamethasone in the control of pyruvate kinase activity and glucose metabolism in sheep adipose tissue.

1. The Vmax. activity of pyruvate kinase of sheep adipose tissue increased during tissue culture up to 48 h; the increase was blocked by actinomycin D (an inhibitor of transcription) and was promoted by insulin and antagonized by dexamethasone. 2. In contrast with their effects on pyruvate kinase, insulin and dexamethasone acted synergistically to increase the activity of glucose-6-phosphate dehydrogenase of sheep adipose tissue maintained in culture. 3. Insulin stimulated, whereas dexamethasone inhibited, glucose utilization by sheep adipose tissue maintained in culture; the two agents were mutually antagonistic, and their effects were prevented by actinomycin D. 4. Antimycin A (an inhibitor of the electron-transport chain) stimulated glucose uptake and lactate output by sheep adipose tissue in the presence of dexamethasone and insulin, suggesting that the effects of dexamethasone on glucose utilization by sheep adipose tissue were not due to an inhibition of glucose transport. 5. Comparison of these findings with previous studies on the endocrine control of hepatic pyruvate kinase shows that there are major differences in the control of these Vmax. activities in liver and adipose tissue. 6. Although glucocorticoid hormones inhibit glucose utilization themselves and can antagonize the stimulatory effects of insulin on glucose utilization in adipose tissue from both sheep and rats, there appear to be major differences in the sites of action of these hormones in the two species.

Metabolic effects of acute and prolonged growth hormone deficiency in streptozotocin-diabetic rats.

To determine whether endogenous GH contributes to impairments of glucose metabolism in diabetes mellitus, we examined the metabolic consequences of GH deficiency in streptozotocin (SZ)-diabetic rats. Diabetic rats were treated with a highly specific antirat GH serum (ArGH) to neutralize the activity of circulating GH, and glucose metabolism was measured in adipose tissue in vitro in the absence or presence of insulin. Short term (6-h) GH deficiency led to a 10% decrease in hyperglycemia (P = 0.002) in SZ-diabetic rats. Basal glucose oxidation and insulin responses in adipose tissue were unchanged by acute ArGH treatment. Since hyperglycemia was improved when adipose tissue metabolism was unaltered, GH-dependent changes occurring in other tissues, such as liver or muscle, most likely contribute to derangements of glucose metabolism in diabetes, even when GH is not elevated. Prolonged GH deficiency was produced by infusing ArGH into SZ-diabetic rats for 5 days. In these animals, the relative fat content (percentage of wet weight) of adipose tissue was significantly increased. In addition, the conversion of [14C]glucose to lipid and CO2 in adipose tissue was significantly increased with chronic GH deficiency in SZ-diabetic rats, but the ability of insulin to stimulate glucose metabolism in the tissue was unaffected. These results indicate that endogenous GH suppresses basal glucose utilization in adipose tissue of diabetic animals; this is reversed by prolonged (5-day), but not acute (6-h), ArGH treatment. Taken together, these findings suggest that the role of endogenous GH in the regulation of glucose metabolism in diabetic animals involves several mechanisms and multiple tissues.

Comparisons of Lipogenesis and Glucose Metabolism between Ovine and Bovine Adipose Tissues

Studies were initiated to compare glucose and lipid metabolism in vitro in subcutaneous adipose tissue of mature sheep and cattle. Mean adipocyte volume was significantly less in subcutaneous adipose tissue of sheep than in adipose tissue from cattle. The presence of acetate and lactate in the incubation medium increased total glucose utilization two- to three-fold in ovine adipose tissue, but had no effect on total glucose utilization in adipose tissue from cattle. Acetate provided 72–82% of the acetyl units to lipogenesis, depending on species and substrate concentration. There were no significant (P > 0.05) differences in the contribution of the pentose cycle to the provision of reducing equivalents to fatty acid biosynthesis, based on the incorporation of label from [3-3H]glucose into fatty acids. In ovine adipose tissue, acetyl-CoA carboxylase appeared to be rate-limiting to lipogenesis, while in bovine subcutaneous adipose tissue, the activity of fatty acid synthetase may have been the limiting step in lipogenesis. In addition, the low activity of ATP-citrate lyase, especially relative to aconitate hydratase, probably limited the conversion of lactate to fatty acids in ovine adipose tissue. It is unlikely that ATP-citrate lyase activity was rate-limiting to lipogenesis from lactate in bovine adipose tissue. The data indicate that extending the results obtained from adipose tissue from one species to lipid metabolism in ruminants in general may not be valid.

Effects of streptozotocin diabetes and insulin treatment on adipose tissue glucose utilization in the rat.

[U-14C] glucose utilization by pieces of epididymal fat-pad was studied in streptozotocin-diabetic rats, food-restricted animals, and normal controls. Both CO2 and fatty acids formation were greatly reduced in tissues from the diabetic animals treated or not with insulin and this change was milder in tissues from food-restricted rats. A positive correlation was found between [14C] glucose utilization in vitro and plasma RIA-insulin levels when values from all animals were pooled. The percentual response to high doses of insulin was small in adipose tissue from streptozotocin-diabetic animals for CO2 and total lipids formation, but it was high for fatty acids synthesis; the response in food-restricted animals was high and was greatly augmented in tissues from the streptozotocin-diabetic rats treated with insulin. Results indicate that in adipose tissue from streptozotocin-diabetic animals the alteration of insulin responsiveness occurs distal to the receptor events and that impaired basal glucose metabolism is a direct consequence of their hypoinsulinemia.

Insulin-stimulated glucose utilization in adipose tissue from rats bearing Walker 256 carcinoma

Male Sprague-Dawley rats (125–150 g) were implanted intramuscularly with Walker 256 carcinoma. After 10–14 days, tumor-bearing rats, along with controls, were killed and the ability of insulin to promote the in vitro utilization of glucose by epididymal adipose tissue was assessed. The sensitivity of free adipocytes and minced adipose tissue from tumor-bearing rats to insulin, as assessed by measurement of the incorporation of glucose into total lipids as well as into the triglyceride fraction of neutral lipids, was significantly less ( P < 0.01) as compared to control animals. Similarly, insulin was considerably less effective at enhancing glycogenesis in vitro in adipose tissue from animals bearing the tumor for 10 days compared to adipose tissue from controls. Adipose tissue from tumor-bearing animals tended to convert less glucose to CO 2 in the presence of insulin than did adipose tissue from controls. That this decreased in vitro sensitivity to insulin of adipose tissue from tumor-bearing animals could be the result of simple down-regulation by high levels of circulating insulin can be ruled out by the fact that the presence of the tumor resulted in lower circulating insulin than that in control animals. Serum glucose levels were also lower in tumor-bearing rats than in corresponding control animals.

Adrenaline responsiveness of glucose metabolism in insulin-resistant adipose tissue of rats fed a high-fat diet.

The effects of adrenaline (0.5 microM) and the combination of adrenaline and insulin (1.7nM) on [6-14C]glucose metabolism were assessed in epididymal fat-pads from rats fed either a low- or high-fat diet. The response of lipolysis to adrenaline was clearly diminished in fat-fed rats. Insulin added to adrenaline inhibited the lipolysis by 50% regardless of the diet. Glucose utilization in adipose tissue of fat-fed rats was markedly stimulated by adrenaline (glucose uptake was increased 3-fold and the production of CO2 and the glycerol moiety of acylglycerol was increased 4-fold). However, adipose tissue from fat-fed rats was resistant to the effect of insulin to produce a further increase in adrenaline-stimulated glucose uptake. The intracellular capacity of lipogenesis on the one hand, and the production of CO2 and the glycerol moiety of acylglycerol on the other, are of prime importance in the action of insulin and adrenaline on glucose utilization in this model.

Effect of Dietary Fructose on Free Fatty Acid Release from Adipose Tissue and Serum Free Fatty Acid Concentration in the Rat

The administration of a diet, containing 70 cal% of fructose, increases in rats, as compared with a diet containing 70 cal% of glucose, the release of free fatty acids (FFA) from adipose tissue in vitro. Since the glycerol release from adipose tissue is not increased by the high fructose diet, it may be concluded that the enhanced FFA release in the fructose group is due to a reduced re-esterification of FFA in adipose tissue rather than to an enhanced hpolysis. The serum concentrations of FFA are increased by fructose intake temporarily (for the first week of the diet administration), the increased FFA release from adipose tissue being present up to 1 month after starting the diet. The reduced re-esterification of FFA in fructose-fed rats is probably connected with the reduced glucose utilization in adipose tissue. None of the described effects of the fructose diet seems to result from insulin deficiency since no difference was found in the serum insulin concentrations between the groups on the fructose and glucose diet. It is speculated whether the enhanced FFA release from adipose tissue in rats fed the fructose diet may participate in the mechanism of fructose-induced hypertriglyceridaemia.

Sequential changes in glucose metabolism by adipose tissue and liver of rats after destruction of the ventromedial hypothalamic muclei: Effect of three dietary regimens

U- 14C-glucose metabolism by adipose tissue and liver was studied in vitro at several time periods after destruction of the ventromedial hypothalamic nuclei (VMN) in weanling rats on three dietary regimens. In addition, plasma insulin and glucose, food intake, carcass composition, and weight gain were measured. The animals fed ad lib, comprising experimental series I, were sacrificed at varying intervals from 2 to 13 days after lesion placement. Results in rats with lesions showed: an initial depression in food intake by lesioned animals; hyperinsulinemia and increased lipogenesis by liver and adipose tissue during a period of hypophagia; a delay of several days before increased glucose oxidation became apparent; and difference between the responses of liver and adipose tissue to lesioning. Animals in experimental series II were tube fed a quantity of diet inadequate to maintain body weight (semistarvation). This suppressed all metabolic and hormonal alterations that normally accompany VMN destruction. In experimental series III, all animals were tube fed a sufficient quantity of diet to insure weight gain in an attempt to standardize food intake and feeding pattern. Rats with lesions demonstrated: an increase in fatty acid labeling by liver 24 hr postoperatively, accompanied by hyperinsulinemia and hyperglycemia; asynchronous enhancement of glucose utilization, such that liver glucose oxidation was not elevated until 24 hr after an increase in liver lipogenesis; and delay in the increase in adipose tissue glucose utilization until 72 hr after the elevation of plasma insulin and glucose.

A defect of glucose utilization in adipose tissue of adult diabetics and in some conditions which may predispose to diabetes.

1. The effects of glucose, glucose 6-phosphate, and l-glycerol 3-phosphate on the incorporation of [1-14C]palmitate into neutral lipid have been studied in homogenates of adipose tissue obtained from adult diabetics and control patients. In the diabetic, glucose, glucose 6-phosphate and l-glycerol 3-phosphate supported incorporation of 19, 27 and 62% of total counts respectively; whereas in paired non-diabetic controls the respective values were 78, 80 and 84%. 2. Confirmation of these results were provided by finding slower rates of conversion of [U-14C]glucose into phosphate esters in diabetic adipose tissue compared to paired non-diabetic controls. Rates were improved but not restored to normal by treatment of diabetic patients with insulin. 3. These results could not be explained on the basis of differences in isotope dilution in precursor pools or to the presence of raised levels of free fatty acids in diabetic tissue. 4. A group of latent diabetics showed a pattern of substrate utilization more like fully developed diabetes than non-diabetic controls. Rates of glucose phosphorylation were slower in latent diabetics than in paired controls. 5. Studies were also performed with homogenates of adipose tissue prepared from patients with Cushing's disease, obesity and pregnancy, these groups being predisposed to develop adult diabetes. 6. In Cushing's disease (eight patients) glucose, glucose 6-phosphate and l-glycerol 3-phosphate supported incorporation of 9 ± 1 (13), 19·2 ± 3·9 (10) and 23·2 ± 3·3 (9)% of total counts at 2 hr respectively; whereas in paired controls respective values were 19·7 ± 3·4 (10), 25·7 ± 2·8 (10) and 26·4 ± 2·9 (10)%. Support for these results was provided by finding slower rates (by about 50%) of conversion of [U-14C]glucose into phosphate esters in tissue from Cushing's disease compared to paired controls. 7. Ten obese patients with no clinical evidence of diabetes showed a pattern of substrate utilization more like diabetic adipose tissue; whereas another eight obese patients resembled their non-obese controls. 8. Adipose tissue from six pregnant patients (over 10 weeks) showed a diabetic pattern of substrate utilization; and confirmation was provided by rates of [U-14C]glucose conversion into phosphate esters (as counts × 10 min−1 mg protein−1 hr−1) of 929 ± 75 (5) in pregnancy versus 1386 ± 198 (5) in paired controls.