Increased Plasma FFA Research Articles

GLUT4 degradation by GLUTFOURINH® in mice resembles moderate-obese diabetes of human with hyperglycemia and low lipid accumulation

Backgrounds and aimsType 2 diabetes mellitus (T2D) is a chronic disease characterized by insulin resistance and hyperglycemia. To investigate T2D, genetic and chemical induced hyper-obese rodent models have been experimentally developed. However, establishment of moderate-obese diabetes model will confer diverse opportunities for translational studies. In this study, we found the chemical, GLUTFOURINH® (GFI), induces post-translational degradation of glucose transporter 4 (GLUT4). We aimed to establish novel diabetic model by using GFI. Methods and resultsLow plasma membrane GLUT4 (pmGLUT4) levels by GFI resulted in reduction of intracellular glucose uptake and TG, and increase of intracellular FFA in A204 cells. Likewise, GFI treatment decreased intracellular TG and increased intracellular FFA levels in Hep3B and 3T3-L1 cells. Mice were administered with GFI (16 mg/kg) for short-term (3-day) and long-term (28- and 31-day) to compared with vehicle injection, HFD model, and T2D model, respectively. Short-term and long-term GFI treatments induced hyperglycemia and hyperinsulinemia with low pmGLUT4 levels. Compared to HFD model, long-term GFI with HFD reduced adipose weight and intracellular TG accumulation, but increased plasma FFA. GFI treatment resulted in insulin resistance by showing low QUICKI and high HOMA-IR values, and low insulin response during insulin tolerance test. Additionally, low pmGLUT4 by GFI heightened hyperglycemia, hyperinsulinemia, and insulin resistance compared to T2D model. ConclusionsIn summary, we report GLUT4 degradation by novel chemical (GFI) induces moderate-obese diabetes representing hyperglycemia, insulin resistance and low intracellular lipid accumulation. The GLUT4 degradation by GFI has translational value for studying diseases related to moderate-obese diabetes.

54-LB: Distinct Mechanisms Are Responsible for the Increase in Endogenous Glucose Production and Ketone Formation following Empagliflozin in T2DM Patients

Aim: To examine the mechanisms responsible for the increase in glucose and ketone production caused by SGLT2 inhibition with empagliflozin in T2DM patients. Research Design and Methods: 12 T2DM subjects (Age = 53; BMI = 31.7; HbA1c = 7.4%) participated in two studies performed in random order. At 0700h following an overnight fast subjects received an 8-hour infusion of 6,6D2-glucose to measure endogenous (hepatic) glucose production. At 0900 h an infusion of 3H-norepinephrine was started. At 1000h subjects ingested 25 mg of empagliflozin (n=8) or matching placebo (n=4) and were followed for 5 hours (1500 h) . Within 1 week subjects returned for a repeat study with pancreatic clamp to maintain plasma insulin and glucagon concentrations constant at the basal level. As per study one, subjects ingested empagliflozin 25 mg or placebo prior to the pancreatic clamp. Results: When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dl) and insulin (-52%) concentrations and increases in plasma glucagon (+19%) , FFA (+29%) and β-hydroxybutyrate (β-HB) (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate increased significantly in subjects receiving empagliflozin (+67%) compared to placebo under both fasting and pancreatic clamp conditions. No difference in plasma norepinephrine concentration was observed in either study. Conclusion: The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is explained by the increase in total-body NE turnover. Disclosure S. Abdelgani: None. J. M. Adams: None. G. Daniele: n/a. F. Almulla: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca. M. Abdul-ghani: None. M. Abu-farha: None. S. Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. Funding National Institute of Health, Boehringer Ingelheim provided empagliflozin and placebo

The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization, enhances hepatic β-oxidation, and induces ketosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to increase ketone bodies in patients with type 2 diabetes; however, the underlying mechanisms have not been fully elucidated. Here we examined the effect of the SGLT2 inhibitor dapagliflozin (1 mg/kg/day, formulated in a water, PEG400, ethanol, propylene glycol solution, 4 weeks) on lipid metabolism in obese Zucker rats. Fasting FFA metabolism was assessed in the anesthetized state using a [9,10-3H(N)]-palmitic acid tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and nonoxidative disposal (Rst). In the liver, clearance (Kβ-ox) and flux (Rβ-ox) of FFA into β-oxidation were estimated using [9,10-3H]-(R)-bromopalmitate/[U-14C]palmitate tracers. As expected, dapagliflozin induced glycosuria and a robust antidiabetic effect; treatment reduced fasting plasma glucose and insulin, lowered glycated hemoglobin, and increased pancreatic insulin content compared with vehicle controls. Dapagliflozin also increased plasma FFA, Ra, Rox, and Rst with enhanced channeling toward oxidation versus storage. In the liver, there was also enhanced channeling of FFA to β-oxidation, with increased Kβ-ox, Rβ-ox and tissue acetyl-CoA, compared with controls. Finally, dapagliflozin increased hepatic HMG-CoA and plasma β-hydroxybutyrate, consistent with a specific enhancement of ketogenesis. Since ketogenesis has not been directly measured, we cannot exclude an additional contribution of impaired ketone body clearance to the ketosis. In conclusion, this study provides evidence that the dapagliflozin-induced increase in plasma ketone bodies is driven by the combined action of FFA mobilization from adipose tissue and diversion of hepatic FFA toward β-oxidation.

Photoactivation of Dok1/ERK/PPARγ signaling axis inhibits excessive lipolysis in insulin-resistant adipocytes

Insulin resistance is a hallmark of the metabolic syndrome and type 2 diabetes. Increased plasma FFA level is an important cause of obesity-associated insulin resistance. Over-activated ERK is closely related with FFA release from adipose tissues in patients with type 2 diabetes. Nevertheless, there are no effective strategies to lower plasma FFA level. Low-power laser irradiation (LPLI) has been reported to regulate multiple biological processes. However, whether LPLI could ameliorate metabolic disorders and the molecular mechanisms involved remain unknown. In this study, we first demonstrated that LPLI suppresses excessive lipolysis of insulin-resistant adipocytes by activating tyrosine kinases-1(Dok1)/ERK/PPARγ pathway. Our data showed that LPLI inhibits ERK phosphorylation through the activation of Dok1, resulting in decreased phospho-PPARγ level. Non-phosphorylated PPARγ maintains in nucleus to promote the expression of adipogenic genes, reversing excessive lipolysis in insulin-resistant adipocytes. In summary, the present research highlights the important roles of Dok1/ERK/PPARγ pathway in lowering FFA release from adipocytes, and our research extends the knowledge of the biological effects induced by LPLI.

Postprandial Spillover of Dietary Lipid into Plasma Is Increased with Moderate Amounts of Ingested Fat and Is Inversely Related to Adiposity in Healthy Older Men1–3

Adverse effects on health mediated by increased plasma FFA concentrations are well established and older individuals are particularly susceptible to these effects. We sought to determine the effects of the amount of dietary fat on increasing the plasma FFA concentrations as a result of “spillover” of dietary fat into the plasma FFA pool during the postprandial period in older men. Healthy, older participants (63–71 y old) were studied in a randomized, crossover design following ingestions of low (LF) and moderate (MF) amounts of [1,1,1-13C]-triolein-labeled fat, corresponding to 0.4 and 0.7 g of fat/kg body weight, respectively. Spillover of dietary fatty acids into plasma during the 8-h postprandial period (AUC; mmol · L-1 · h) after MF ingestion was 1.2 times greater than that after LF ingestion (2.8 ± 0.4 vs. 1.2 ± 0.1; P < 0.05). The spillover of dietary fatty acids following the MF, but not the LF, ingestion was correlated with the percent body fat (rs = -0.89) and percent body fat-free mass (rs = 0.94) of the men (P < 0.05). After adjusting to the amount of ingested fat, the spillover of dietary fatty acids in the MF trial was disproportionally higher than that in the LF trial (P < 0.05), but the corresponding postprandial plasma TG responses did not differ between trials. In conclusion, spillover of dietary lipid into plasma is disproportionally increased at higher doses of dietary fat and this response is inversely related to adiposity in healthy men of advanced age.

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipid-lowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (>60%, P < 0.01), and this effect was maintained for ≥5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P < 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment.

Free fatty acids and acute coronary syndromes--the history

While it has been known for >40 years that elevation of plasma-free fatty acids (FFAs or non-esterified fatty acids, NEFA) occurs within 1 or 2 h of the onset of an acute coronary syndrome (ACS) and that the greater the increase in plasma FFA the greater the incidence of serious ventricular arrhythmias, no account exists as to how this was discovered and developed. It was derived from analysis of serum lipoproteins. In 1949, Cohn and colleagues, using elaborate low temperature fractionation, reported that almost all the plasma lipids circulate in combination with proteins, particularly the α- and β-globulin fractions1; these were therefore termed α- and β-lipoproteins.2 A more simple method of analysis is zone electrophoresis of serum lipoproteins in a starch block.3 Using lipid stains, it was possible to identify cholesterol-carrying β-lipoproteins [low-density lipoproteins (LDL)] and α-lipoproteins [or high-density lipoproteins (HDL)]. But these methods required many milliliters of serum, so we developed a micro method applying 0.15 ml of serum to Whatman filter paper using sudan IV or oil red O as the lipid stain. The precise analytical method based on cholesterol elution from the electrophoretic bands reacting to protein staining with bromophenol blue was described in detail in 1954.4 It provided the basis of our report in 1955 that, compared with age-matched …

The Role of Snacking in Energy Balance: a Biobehavioral Approach ,

Snacking is often presumed to contribute to obesity, but to date, studies have not demonstrated such a causal relationship, probably because a clear definition of snacking is still elusive. The usual one, i.e. any intake between traditional meals, has no physiological basis. Moreover, because some evidence suggests that frequent meals may prevent overweight, any confusion between snacks and meals may mask the deleterious effect of snacks on energy balance. Therefore, we developed a biobehavioral approach to assess whether objective criteria for eating a meal and snacking could be determined. Our main findings were that regardless of the time of consumption or macronutrient composition, snacks exerted a weak satiety effect, with those higher in protein having the strongest. The energy content of snacks was never compensated for at the next meal and led consistently to a positive energy balance compared with no-snack conditions. Biologically, the snack-induced insulin secretion suppressed the late increase in plasma FFA, which may have contributed to the inhibition of satiety. Lastly, snacking was not preceded by the glucose and insulin profile observed prior to a spontaneously requested meal. In conclusion, further studies on the role of snacking in energy balance should include criteria other than nutrient composition or consumption between meals for defining these eating occasions as snacks.

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

BackgroundCVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects.Methods40 non-diabetic subjects (age = 38 ± 3 yr, BMI = 28 ± 1 kg/m2, FPG = 95 ± 1 mg/dl, HbA1c = 5.3 ± 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I).ResultsLipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 ± 10 vs. 186 ± 25 ng/ml), VCAM-1 (1066 ± 67 vs. 1204 ± 65 ng/ml) and sE-S (20 ± 1 vs. 24 ± 1 ng/ml) between 13-35% and by ≥ 2-fold plasma levels of myeloperoxidase (7.5 ± 0.9 to 15 ± 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 ± 0.6 to 22.5 ± 1.5 ng/ml), an indicator of a prothrombotic state (all p ≤ 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects.ConclusionsAn increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.

Chronic Low‐Dose Lipid Infusion in Healthy Patients Induces Markers of Endothelial Activation Independent of Its Metabolic Effects

Elevated plasma triglyceride/free fatty acid (FFA) levels and insulin resistance may promote atherosclerosis through endothelial activation (ie, increased expression of intercellular adhesion molecule 1 [ICAM-1]/vascular adhesion molecule 1 [VCAM-1], and endothelin-1 [ET-1]) in patients with the metabolic syndrome, but this has never been directly tested. The authors measured endothelial activation and insulin sensitivity (euglycemic insulin clamp with [3-(3)H]-glucose) after a 4-day low-dose lipid infusion that elevated plasma FFA to levels observed in the metabolic syndrome in 20 lean, non-diabetic insulin-resistant subjects with a strong family history of type 2 diabetes mellitus (FH(+)) and 10 insulin-sensitive volunteers without a family history of type 2 diabetes mellitus (FH(-)). Low-dose lipid infusion reduced insulin sensitivity by approximately 25% in insulin-sensitive FH(-)controls but did not worsen preexisting insulin resistance in FH(+). Low-dose lipid infusion elevated plasma ICAM and VCAM levels similarly in both groups (approximately 12%-18%; P<.01 vs baseline), while plasma ET-1 levels increased more in FH(+)vs FH(-)(46% vs 10%; P=.005). Increased plasma FFA levels closely correlated with elevated ICAM (r=0.60; P<.01), VCAM, and ET-1 levels (r=0.39 and r=0.42, respectively; P<.05). Low-dose lipid infusion induces endothelial activation in both lean insulin-resistant (FH(+)) and insulin-sensitive (FH(-)) healthy patients, regardless of changes in insulin sensitivity. These results prove that even a modest lipid oversupply may be sufficient to trigger a deleterious endothelial response.

High-Fat Diet–Induced Neuropathy of Pre-Diabetes and Obesity

Subjects with dietary obesity and pre-diabetes have an increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal models of this type of neuropathy have not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed a high-fat diet (HFD), a model of pre-diabetes and alimentary obesity. Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks. HFD-fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They also had motor and sensory nerve conduction deficits, tactile allodynia, and thermal hypoalgesia in the absence of intraepidermal nerve fiber loss or axonal atrophy. Despite the absence of overt hyperglycemia, the mice displayed augmented sorbitol pathway activity in the peripheral nerve, as well as 4-hydroxynonenal adduct nitrotyrosine and poly(ADP-ribose) accumulation and 12/15-lipoxygenase overexpression in peripheral nerve and dorsal root ganglion neurons. A 6-week feeding with normal chow after 16 weeks on HFD alleviated tactile allodynia and essentially corrected thermal hypoalgesia and sensory nerve conduction deficit without affecting motor nerve conduction slowing. Normal chow containing the aldose reductase inhibitor fidarestat (16 mg x kg(-1) x day (-1)) corrected all functional changes of HFD-induced neuropathy. Similar to human subjects with pre-diabetes and obesity, HFD-fed mice develop peripheral nerve functional, but not structural, abnormalities and, therefore, are a suitable model for evaluating dietary and pharmacological approaches to halt progression and reverse diabetic neuropathy at the earliest stage of the disease.

CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance

CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient (cd36(-)(/)(-)) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36(-)(/)(-) mice. cd36(-)(/)(-) mice showed no differences in hepatic VLDL-TG production or intestinal [(3)H]TG uptake compared with wild-type littermates. cd36(-)(/)(-) mice showed a 2-fold enhanced postprandial TG response upon an intragastric fat load (P < 0.05), with a concomitant 2.5-fold increased FFA response (P < 0.05), suggesting that the increased FFA in cd36(-/-) mice may impair LPL-mediated TG hydrolysis. Postheparin LPL levels were not affected. However, the in vitro LPL-mediated TG hydrolysis rate as induced by postheparin plasma of cd36(-)(/)(-) mice in the absence of excess FFA-free BSA was reduced 2-fold compared with wild-type plasma (P < 0.05). This inhibition was relieved upon the addition of excess FFA-free BSA. Likewise, increasing plasma FFA in wild-type mice to the levels observed in cd36(-)(/)(-) mice by infusion prolonged the plasma half-life of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles by 2.5-fold (P < 0.05). We conclude that the increased plasma TG levels observed in cd36(-)(/)(-) mice are caused by decreased LPL-mediated hydrolysis of TG-rich lipoproteins resulting from FFA-induced product inhibition of LPL.

Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid

The resistin gene is expressed in adipocytes and encodes a protein proposed to link obesity and type 2 diabetes. Increased plasma FFA is associated with insulin resistance. We examined the effect of separate FFAs on the expression of resistin mRNA in cultured murine 3T3-L1 adipocytes. The FFAs tested did not increase resistin expression, whereas both arachidonic acid (AA) and eicosapentaenoic acid (EPA) reduced resistin mRNA levels. AA was by far the most potent FFA, reducing resistin mRNA levels to approximately 20% of control at 60-250 muM concentration. Selective inhibitors of cyclooxygenase-1 and of mitogen-activated protein kinase kinase counteracted AA-induced reduction in resistin mRNA levels. Transient overexpression of sterol-regulatory element binding protein-1a (SREBP-1a) activated the resistin promoter, but there was no reduction in the abundance of approximately 65 kDa mature SREBP-1 after AA exposure. Actinomycin D as well as cycloheximide abolished the AA-induced reduction of resistin mRNA levels, indicating dependence on de novo transcription and translation. Our data suggest that reductions in resistin mRNA levels involve a destabilization of the resistin mRNA molecule. An inhibitory effect of AA and EPA on resistin expression may explain the beneficial effect of ingesting PUFAs on insulin sensitivity.

Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance in liver and muscle and impaired insulin secretion. Considerable evidence also implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in T2DM. 1) Fat cells are resistant to insulin’s antilipolytic effect, leading to day-long elevated plasma FFA levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic/muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. 2) Dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines. 3) Enlarged fat cells are insulin resistant and have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid “overflows” into muscle, liver, and perhaps -cells, causing muscle/ hepatic insulin resistance and impaired insulin secretion. Thiazolidinediones enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA, and favorably influence the production of adipocytokines. Thiazolidinediones also redistribute fat within the body (decreased visceral and hepatic fat; increased sc fat) and decrease intracellular concentrations of triglyceride metabolites in muscle, liver, and -cells, contributing to improvements in muscle/hepatic insulin sensitivity and pancreatic function in type 2 diabetics.

The leptin-like effects of 3-d peripheral administration of a melanocortin agonist are more marked in genetically obese Zucker (fa/fa) than in lean rats.

The effects of a 3-d peripheral administration of an alpha-MSH agonist, MTII, on body weight and the expression of uncoupling proteins (UCPs) and carnitine palmitoyltransferase-1 were determined in lean and genetically obese fa/fa rats by comparing MTII-treated animals with two different control groups, one being ad libitum fed, the other pair-fed to the amount of food consumed by MTII-treated rats. MTII treatment of lean and obese rats lowered food intake and body weight, the effects being more marked in obese than in lean rats. In both groups, MTII administration suppressed the increased plasma FFA levels brought about by food restriction. In lean rats, MTII prevented the decrease in brown adipose tissue UCP1, UCP2, and UCP3 expression and muscle UCP3 occurring during food restriction. In obese animals, MTII markedly increased brown adipose tissue (7-fold) and muscle (2.5-fold) UCP3 expression. The decrease in liver carnitine palmitoyltransferase-1 elicited by food restriction in lean and obese rats was prevented by MTII administration. In summary, the effects of MTII resemble those of leptin and are more marked in obese than in lean animals, in keeping with their reported reduced endogenous melanocortin tone. Melanocortin agonists may be useful in the treatment of obesity associated with impaired leptin signaling.

The Leptin-Like Effects of 3-d Peripheral Administration of a Melanocortin Agonist Are More Marked in Genetically Obese Zucker (fa/fa) than in Lean Rats

The effects of a 3-d peripheral administration of an α-MSH agonist, MTII, on body weight and the expression of uncoupling proteins (UCPs) and carnitine palmitoyltransferase-1 were determined in lean and genetically obese fa/fa rats by comparing MTII-treated animals with two different control groups, one being ad libitum fed, the other pair-fed to the amount of food consumed by MTII-treated rats. MTII treatment of lean and obese rats lowered food intake and body weight, the effects being more marked in obese than in lean rats. In both groups, MTII administration suppressed the increased plasma FFA levels brought about by food restriction. In lean rats, MTII prevented the decrease in brown adipose tissue UCP1, UCP2, and UCP3 expression and muscle UCP3 occurring during food restriction. In obese animals, MTII markedly increased brown adipose tissue (7-fold) and muscle (2.5-fold) UCP3 expression. The decrease in liver carnitine palmitoyltransferase-1 elicited by food restriction in lean and obese rats was prevented by MTII administration. In summary, the effects of MTII resemble those of leptin and are more marked in obese than in lean animals, in keeping with their reported reduced endogenous melanocortin tone. Melanocortin agonists may be useful in the treatment of obesity associated with impaired leptin signaling.

Pancreatic beta-cell alpha2A adrenoceptor and phospholipid changes in hyperlipidemic rats.

We previously showed that a 48-h intravenous lipid infusion in rats induces pancreatic beta-cell hypersensitivity to catecholamines. Our aim was to study the lipid-related changes that may account for such hypersensitivity in pancreatic islets. We show here that a 48-h increase in plasma FFA alters the binding characteristics of beta-cell alpha2 adrenoceptors in rats. Lipid infusion decreases pancreatic norepinephrine (NE) turnover rate by 28%, reflecting a reduction of pancreatic NE stores. Following lipid infusion, the density of alpha2 adrenoceptor binding sites is significantly lower and receptor affinity higher, both in islet homogenates (by three- and fivefold, respectively) and isolated whole beta-cells (by two- and sixfold, respectively). These changes correlate with the elevated insulin response to glucose found in lipid-infused rats. We also found a modification of islet phospholipid content, particularly in phosphoethanolamine species containing infused FA such as palmitate, oleate, stearate, and linoleate. This may account for the modifications in receptor affinity. These results suggest that hyperlipidemia-associated pathologies such as diabetes and obesity not only may result from alterations of metabolic pathways but also may be a consequence of early modifications in nervous firing rates and signal transduction pathways.

Low adipocyte IRS-1 expression is associated with both insulin resistance and increased plasma FFA levels in response to stress

Low adipocyte IRS-1 expression is associated with both insulin resistance and increased plasma FFA levels in response to stress

Effects of Phosphate Injection on Metabolic and Hormonal Responses to Exercise in Fructose-Injected Rats

GHANBARI–NIAKI, A., F. DÉSY AND J.-M. LAVOIE. Effects of phosphate injection on metabolic and hormonal responses to exercise in fructose-injected rats. PHYSIOL BEHAV 67(5) 747–752, 1999.—The purpose of the present study was to evaluate the effects of an intraperitoneal injection of sodium phosphate on the metabolic and hormonal responses to exercise. Fructose-injected rats were either injected with sodium phosphate (Na 2HPO 4) or NaCl, either in a fed or in a food-restricted state (24 h), and evaluated at rest or after a 30-min exercise period (26 m/min; 0% grade). Liver ATP, phosphate (Pi), and glycogen concentrations were, on the whole, significantly ( p < 0.05) higher in Na 2HPO 4 than in NaCl groups. Exercise resulted in a significant ( p < 0.01) decrease in liver ATP and glycogen levels in fed and food-restricted rats whether injected with NaCl or Na 2HPO 4. Exercise, after NaCl and Na 2HPO 4 injection, resulted in a significant ( p < 0.01) increase in liver phosphate and Pi/ATP ratio, and in a decrease in glucose and an increase in glucagon levels in food-restricted rats only. The normal exercise-induced increase in plasma FFA, glycerol, and norepinephrine levels ( p < 0.05), observed in both fed and food-restricted NaCl-injected rats, was abolished by the injection of phosphate. The data are in line with the new concept that in addition to blood glucose levels, the increase in liver Pi/ATP ratio could also contribute to the increase in glucagon response during exercise.

Effects of phlorizin and acipimox on insulin resistance in STZ-diabetic rats.

To evaluate the roles of hyperglycemia and increased plasma FFA level in the development of insulin resistance, we examined the effects of phlorizin and acipimox treatments on tissue sensitivity to insulin in streptozotocin(STZ)-diabetic rats. Insulin sensitivity was assessed with the glucose-insulin clamp technique. Blood glucose concentration was clamped at basal levels of control and diabetic states, and plasma insulin concentrations were clamped at the levels of basal, approximately 60 and approximately 1500 microU/ml. In diabetic rats, the basal blood glucose and plasma FFA levels in the fasting state were elevated, while the plasma insulin concentration was lower than in normal controls. Moreover, diabetic rats became glucose intolerant after intravenous injection of glucose. The metabolic clearance rate(MCR) of glucose showed a decrease of basal and insulin stimulated response in diabetic rats. As results of the glucose-insulin clamp study and intravenous glucose tolerance test, insulin resistance was developed in STZ-diabetic rats. Phlorizin treatment of diabetic rats recovered insulin sensitivity to nearly normal levels and improved glucose tolerance, but had no effect on insulin action in controls. Insulin sensitivity was also improved by acipimox treatment in diabetic rats, but did not reach normal levels. These results show that hyperglycemia is an obvious causative factor of insulin resistance, and increased FFA level may also act on the development of insulin resistance in STZ-diabetic rats.