Developmental trajectories of metacognitive processing and executive function from childhood to older age.

The modern understanding of the term metacognition encompasses two levels of processing: a lower level awareness or knowledge of one's own thoughts and a higher level regulation or control of our thinking. Metacognition, therefore, bears conceptual similarity with executive function: both are concerned with top-down monitoring and control of cognition in the service of ongoing goal-directed behaviour. Previous studies have shown a possible executive function advantage in multilingual speakers but also a possible disadvantage in metacognitive processing. To progress theory on metacognitive processing and the relationship with executive function and linguistic experience across the lifespan, we conducted a study testing 330 healthy individuals in four age groups from 7 to 80 years old. All participants performed a metacognition task and two measures of executive function, which included the Simon task and the Tower of London task. Half the participants were multilingual speakers since birth. We built developmental trajectories of metacognitive and executive function across the lifespan. The best metacognitive efficiency was observed in mid-adulthood, whereas the best executive function processing reached its peak in young adulthood. A steep cognitive decline was observed in older age, while metacognitive efficiency was preserved. Exploratory factor analysis indicated that metacognition and executive function are served by different factors across all ages. Contrary to previous findings in the bilingual literature, a multilinguistic experience conferred neither any significant advantage nor disadvantage in both executive function and metacognitive processing across the lifespan.

A role for the cerebellum in the control of verbal interference: Comparison of bilingual and monolingual adults.

We evaluate brain structure sensitivity to verbal interference in a sentence interpretation task, building on previously reported evidence that those with better control of verbal interference show higher grey matter density in the posterior paravermis of the right cerebellum. We compare brain structure sensitivity to verbal interference control across two groups, English monolingual (N = 41) and multilingual (N = 46) adults. Using voxel-based morphometry, our primary goal was to identify and explore differences in regional patterns of grey matter sensitivity to performance on the sentence interpretation task, controlling for group variability in age, nonverbal reasoning and vocabulary knowledge. There was no group difference in performance but there was a significant group effect in grey matter sensitivity to task performance in our region of interest: stronger sensitivity in the paravermis in bilinguals compared to monolinguals in accuracy performance in the high (relative to low) verbal interference condition. This effect was observed when the linguistic interference was presented in an unfamiliar language (Greek) but not when presented in the familiar language (English). Our findings suggest that multilanguage acquisition mediates regional involvement within the language network, conferring enhanced functional plasticity within structures (including the paravermis) in the service of control of linguistic interference.

Developmental trajectories of control of verbal and non-verbal interference in speech comprehension in monolingual and multilingual children.

Research on speech comprehension in noise indicates that a multilinguistic experience may confer advantages in filtering out verbal interference, an effect observed both in children acquiring two or more languages since birth (Filippi, Morris, Richardson, et al., 2015) and in second language learner adults (Filippi, Leech, Thomas, et al., 2012). A possible interpretation for this advantage is that the multilingual mind is "trained" to control interference from the language not in use. This constant effort may support optimization of cognitive resources that are necessary for successfully selecting, processing and interpreting complex linguistic information. The present study aimed to extend this line of research by including a non-verbal interference condition. 209 typically developing children (132 English monolinguals and 77 multilinguals from different linguistic backgrounds) carried out a sentence interpretation task in the presence of verbal and non-verbal interference. We found no evidence for a reliable group difference in our data. Instead, findings indicated that background cognitive ability and socioeconomic status were the best indicators of successful control of interference, irrespective of whether participants were bilingual or monolingual. These findings are discussed in the light of previous research and, more widely, on the account of the current debate on the bilingual advantage.

Evidence against a cognitive advantage in the older bilingual population.

Recent evidence has challenged long-standing claims that multi-language acquisition confers long-term advantages in executive function and may protect against age-related cognitive deterioration. We assessed evidence for a bilingual advantage in older monolingual and bilingual residents matched on age, gender, and socioeconomic status. A comprehensive battery of tests was administered to measure non-verbal reasoning, working memory capacity, visuo-spatial memory, response inhibition, problem solving, and language proficiency. Analyses, including Bayes factors, revealed comparable performance in both groups, with no significant differences on any task (and the only trend, found for the Tower of London task performance, indicated a monolingual advantage). Overall, therefore, our findings run counter to the bilingual advantage hypothesis. We consider the implications of our study and offer suggestions for future work in this area.

The Importance of Socioeconomic Status as a Modulator of the Bilingual Advantage in Cognitive Ability.

Between-group variability in socioeconomic status (SES) has been identified as a potentially important contributory factor in studies reporting cognitive advantages in bilinguals over monolinguals (the so called "bilingual advantage"). The present study addresses the potential importance of this alternative explanatory variable in a study of low and high SES bilingual and monolingual performance on the Simon task and the Tower of London (TOL) task. Results indicated an overall bilingual response time advantage on the Simon task, despite equivalent error rates. Socioeconomic status was an important modulator in this effect, with evidence that bilingualism may be particularly important in promoting speed of processing advantages in low status individuals but have little impact in high status individuals. However, there was a monolingual advantage on the TOL test of executive planning ability. Together, our findings run counter to the central assertion of the bilingual advantage account, that the process of multi-language acquisition confers a broad cognitive advantage in executive function. We discuss these findings in the context of SES as an important modulator in published studies advocating a bilingual cognitive advantage.

Mortality Risk in Alcoholic Patients in Northern Italy: Comorbidity and Treatment Retention Effects in a 30-Year Follow-Up Study.

AIMS: To analyse the general and cause-specific mortality over the course of 30 years among subjects treated for alcohol use disorders (AUD) in Northern Italy. METHODS: Cohort of 2499 subjects followed-up for mortality until 31 December 2012. Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were computed to compare the mortality in the cohort with the general population. Cox regression was used to study the effect of psychiatric disorders, burden of physical comorbidity and retention in treatment on mortality, controlling for socio-demographic factors. RESULTS: During the follow-up, 435 deaths occurred. Compared with the general population, alcoholics experienced a 5-fold increased mortality (SMR: 5.53; 95% CI: 5.03, 6.07). Significant excess mortality was observed for a range of specific causes: infections, cancers, cardiovascular, respiratory and digestive system diseases as well as violent causes. In multivariate analysis, the hazard of dying was lower for female gender (hazard ratio [HR]: 0.62; 95% CI: 0.46, 0.84) and for increasing length of retention in treatment (HR for third tertile vs first tertile: 0.43; 95% CI: 0.32, 0.57). Burden of physical comorbidity was associated with increased hazard of dying (HR for 3+ comorbidities vs no comorbidities: 4.40; 95% CI: 2.91, 6.66). Psychiatric comorbidity was not associated with mortality. CONCLUSIONS: Despite the harmful effect of AUD, retention in treatment represented a protective factor against death, suggesting that strategies supporting primary medical- and social-care may effectively reduce premature mortality.

FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance.

FGF21 is a key metabolic regulator modulating physiological processes and its pharmacological administration improves metabolic profile in preclinical species and humans. We used native-FGF21 and a long-acting FGF21 (PF-05231023), to determine the contribution of liver and brown adipose tissue (BAT) towards metabolic improvements in Zucker rats and DIO mice (DIOs). FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling. Through detailed lipidomic analyses of liver metabolites in DIOs, we demonstrate that FGF21 favorably alters liver metabolism. We observed a dose-dependent increase of [(18)F]-FDG-glucose uptake in interscapular BAT (iBAT) of DIOs upon FGF21 administration. Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals. Taken together, we demonstrate the liver as an organ that integrates the actions of FGF21 and provide metabolic benefits of FGF21 in Zucker rats and DIOs. Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F.

GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain in Obese Mice.

The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders.

GLP-1(32-36)amide, a novel pentapeptide cleavage product of GLP-1, modulates whole body glucose metabolism in dogs.

We have previously demonstrated in human subjects who under euglycemic clamp conditions GLP-1(9-36)amide infusions inhibit endogenous glucose production without substantial insulinotropic effects. An earlier report indicates that GLP-1(9-36)amide is cleaved to a nonapeptide, GLP-1(28-36)amide and a pentapeptide GLP-1(32-36)amide (LVKGR amide). Here we study the effects of the pentapeptide on whole body glucose disposal during hyperglycemic clamp studies. Five dogs underwent indwelling catheterizations. Following recovery, the dogs underwent a 180 min hyperglycemic clamp (basal glucose +98 mg/dl) in a cross-over design. Saline or pentapeptide (30 pmol kg(-1) min(-1)) was infused during the last 120 min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30 min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4±2.9 mg kg(-1) min(-1)compared to M of 14.3±1.1 mg kg(-1)min(-1) during the saline infusion (P=0.026, paired t-test; P=0.062, Mann-Whitney U test). During this interval, no significant differences in insulin (26.6±3.2 vs. 23.7±2.5 µU/ml, P=NS) or glucagon secretion (34.0±2.1 vs. 31.7±1.8 pg/ml, P=NS) were observed. These findings demonstrate that under hyperglycemic clamp studies the pentapeptide modulates glucose metabolism by a stimulation of whole-body glucose disposal. Further, the findings suggest that the metabolic benefits previously observed during GLP-1(9-36)amide infusions in humans might be due, at least in part, to the metabolic effects of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9-36)amide in the circulation.

GLP-1-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice.

BACKGROUND: The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome. METHODS AND RESULTS: Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight. CONCLUSIONS: GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome.

GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes.

BACKGROUND: Uncontrolled hepatic glucose production (gluconeogenesis), and glycogenolysis, is a major contributor to the fasting hyperglycemia associated with type 2 diabetes. Here we report the discovery of a C-terminal nonapeptide (FIAWLVKGRamide) derived from GLP-1 that suppresses glucose production and oxidative stress in isolated mouse hepatocytes. The nonapeptide, GLP-1(28-36)amide, was reported earlier to be a major product derived from the cleavage of GLP-1 by the endopeptidase NEP 24.11. METHODS AND RESULTS: Hepatocytes were isolated from the livers of normal and diet-induced obese mice. We find that the GLP-1(28-36)amide nonapeptide rapidly enters isolated mouse hepatocytes by GLP-1 receptor-independent mechanisms, and targets to mitochondria where it inhibits gluconeogenesis and oxidative stress. CONCLUSIONS: These findings suggest that GLP-1 not only acts on a cell surface G-protein coupled receptor activating kinase-regulated signaling pathways, but a small C-terminal peptide derived from GLP-1 also enters cells, targets mitochondria, and exerts insulin-like actions by modulating oxidative phosphorylation. GLP-1(28-36)amide, or a peptide mimetic derived there from, might prove to be a useful treatment for fasting hyperglycemia and metabolic syndrome in type 2 diabetes.

Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis.

GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes.

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Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.

Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPARgamma in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, by increasing the expression and release of adiponectin, an adipokine that activates the fuel-sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPARgamma-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 microM troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 microM, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-d-glucose uptake and the oxidation of exogenous [(14)C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min after the administration of a single dose of troglitazone (10 mg/kg, ip). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPARgamma to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPARgamma-mediated gene transcription.

Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists.

The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPARgamma agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPARgamma. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPARgamma agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPARgamma-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.

Metabolic and hormonal interactions between muscle and adipose tissue.

From the perspective of a muscle physiologist, adipose tissue has long been perceived predominantly as a fuel reservoir that provides muscle and other tissues with NEFA when exogenous nutrients are insufficient for their energy needs. Recently, studies have established that adipose tissue is also an endocrine organ. Among the hormones it releases are adiponectin and leptin, both of which can activate AMP-activated protein kinase and increase fatty acid oxidation in skeletal muscle and probably other tissues. Deficiencies of leptin or leptin receptor, adiponectin and IL-6 are associated with obesity, insulin resistance and a propensity to type 2 diabetes. In addition, a lack of adiponectin has been linked to atherosclerosis. Whether this pathology reflects a deficient activation of AMP-activated protein kinase in peripheral tissues remains to be determined. Finally, recent studies have suggested that skeletal muscle may also function as an endocrine organ when it releases the cytokine IL-6 into the circulation during sustained exercise. Interestingly, one of the apparent effects of IL-6 is to stimulate lipolysis, causing the release of NEFA from the adipocyte. Thus, hormonal communications exist between the adipocyte and muscle that could enable them to talk to each other. The physiological relevance of this cross talk clearly warrants further study.

Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways.

Acrp30/adiponectin is an adipocyte-derived serum protein with important roles in regulation of lipid and glucose metabolism, but which of its isoforms are biologically active remains controversial. We addressed this issue by first characterizing the structure of each individual Acrp30 oligomer and the determinants responsible for multimer formation. Freeze etch electron microscopy showed the trimer to exhibit a ball-and- stick-like structure containing a large globular sphere, an extended collagen stalk, and a smaller sphere on the opposite end of the stalk. The hexamer consists of two adjacent trimeric globular domains and a single stalk composed of collagen domains from two trimers. Although not necessary for trimer formation or stability, two of the three monomers in an Acrp30 trimer are covalently linked by a disulfide bond between cysteine residues at position 22. In contrast, assembly of hexameric and higher molecular weight (HMW) forms of Acrp30 depends upon formation of Cys22-mediated disulfide bonds because their reduction with dithiothreitol or substitution of Cys22 with alanine led exclusively to trimers. HMW and hexamer isoforms of Acrp30 activated NF-kappaB in C2C12 cells, but trimers, either natural, formed by reduction of Acrp30 hexamer, or formed by the C22A mutant, did not. In contrast, incubation of isolated rat extensor digitorum longus with naturally formed Acrp30 trimers or trimeric C22A Acrp30 led to increased phosphorylation of AMP-activated protein kinase-alpha at Thr172 and its activation. Hexameric and HMW Acrp30 could not activate AMP-activated protein kinase. Thus, trimeric and HMW/hexameric Acrp30 activate different signal transduction pathways, and Acrp30 represents a novel example of the control of ligand signaling via changes in its oligomerization state.

Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation.

gACRP30, the globular subunit of adipocyte complement-related protein of 30 kDa (ACRP30), improves insulin sensitivity and increases fatty acid oxidation. The mechanism by which gACRP30 exerts these effects is unknown. Here, we examined if gACRP30 activates AMP-activated protein kinase (AMPK), an enzyme that has been shown to increase muscle fatty acid oxidation and insulin sensitivity. Incubation of rat extensor digitorum longus (EDL), a predominantly fast twitch muscle, with gACRP30 (2.5 micro g/ml) for 30 min led to 2-fold increases in AMPK activity and phosphorylation of both AMPK on Thr-172 and acetyl CoA carboxylase (ACC) on Ser-79. Accordingly, concentration of malonyl CoA was diminished by 30%. In addition, gACRP30 caused a 1.5-fold increase in 2-deoxyglucose uptake. Similar changes in malonyl CoA and ACC were observed in soleus muscle incubated with gACRP30 (2.5 micro g/ml), although no significant changes in AMPK activity or 2-deoxyglucose uptake were detected. When EDL was incubated with full-length hexameric ACRP30 (10 micro g/ml), AMPK activity and ACC phosphorylation were not altered. Administration of gACRP30 (75 micro g) to C57 BL6J mice in vivo led to increased AMPK activity and ACC phosphorylation and decreased malonyl CoA concentration in gastrocnemius muscle within 15-30 min. Both in vivo and in vitro, activation of AMPK was the first effect of gACRP30 and was transient, whereas alterations in malonyl CoA and ACC occurred later and were more sustained. Thus, gACRP30 most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC via activation of AMPK and perhaps other signal transduction proteins.

AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats.

Exercise improves insulin sensitivity. As AMP-activated protein kinase (AMPK) plays an important role in muscle metabolism during exercise, we investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on insulin action in insulin-resistant high-fat-fed (HF) rats. Rats received a subcutaneous injection of 250 mg/kg AICAR (HF-AIC) or saline (HF-Con). The next day, euglycemic-hyperinsulinemic clamp studies were performed. Glucose infusion rate during the clamp was enhanced (50%) in HF-AIC compared with HF-Con rats. Insulin-stimulated glucose uptake was improved in white but not in red quadriceps, whereas glycogen synthesis was improved in both red and white quadriceps of HF-AIC rats. HF-AIC rats also showed increased insulin suppressibility of hepatic glucose output (HGO). AICAR-induced responses in both liver and muscle were accompanied by reduced malonyl-CoA content. Clamp HGO correlated closely with hepatic triglyceride content (r = 0.67, P < 0.01). Thus, a single dose of AICAR leads to an apparent enhancement in whole-body, muscle, and liver insulin action in HF rats that extends beyond the expected time of AMPK activation. Whether altered tissue lipid metabolism mediates AICAR effects on insulin action remains to be determined. Follow-up studies suggest that at least some of the post-AICAR insulin-enhancing effects also occur in normal rats. Independent of this, the results suggest that pharmacological activation of AMPK may have potential in treating insulin-resistant states and type 2 diabetes.