Objective: PGC-1a is a transcriptional co-activator and master regulator of mitochondrial biogenesis. While extensively studied in skeletal and cardiac muscle, recent findings suggest that white adipose tissue PGC-1a plays an important role in regulating glucose homeostasis. The purpose of the present investigation was to evaluate the role of AMPK in regulating PGC-1a and mitochondrial enzymes in mouse epididymal and inguinal subcutaneous adipose tissue. Methods: Mitochondrial protein content and norepinephrine and CL 316,243-induced PGC-1a mRNA expression were studied in mouse epididymal and inguinal adipose tissue from wild-type and AMPK b1 2=2 mice. Results: The protein content and phosphorylation of AMPKa was reduced in epididymal adipose tissue from AMPK b1 2=2 compared to WT mice, concomitant with decreases in PGC-1a and mitochondrial marker proteins. Norepinephrine and CL 316,243-mediated induction of PGC-1a were decreased in cultured epididymal adipose tissue from AMPK b1 2=2 relative to WT mice. In inguinal adipose tissue from AMPK b1 2=2 mice, mitochondrial marker protein content and norepinephrine and CL 316,243-mediated increases in PGC-1a were normal despite reductions in the content and phosphorylation of AMPKa. Conclusions: Norepinephrine-and CL 316,243-mediated induction of PGC-1a and mitochondrial protein expression is regulated by AMPK in epididymal, but not inguinal adipose tissue.
The purpose of this study was to investigate the acute effects of endurance exercise (END; 65% V̇O2peak for 60 min) and high-intensity interval exercise (HIE; four 30 s Wingates separated by 4.5 min of active rest) on cardiorespiratory, hormonal, and subjective appetite measures that may account for the previously reported superior fat loss with low volume HIE compared with END. Recreationally active males (n = 18) completed END, HIE, and control (CON) protocols. On each test day, cardiorespiratory measures including oxygen uptake (V̇O2), respiratory exchange ratio (RER), and heart rate were recorded and blood samples were obtained at baseline (BSL), 60 min after exercise, and 180 min after exercise (equivalent times for CON). Subjective measures of appetite (hunger, fullness, nausea, and prospective consumption) were assessed using visual analogue scales, administered at BSL, 0, 60, 120, and 180 min after exercise. No significant differences in excess postexercise oxygen consumption (EPOC) were observed between conditions. RER was significantly (P < 0.05) depressed in HIE compared with CON at 60 min after exercise, yet estimates of total fat oxidation over CON were not different between HIE and END. No differences in plasma adiponectin concentrations between protocols or time points were present. Epinephrine and norepinephrine were significantly (P < 0.05) elevated immediately after exercise in HIE compared with CON. Several subjective measures of appetite were significantly (P < 0.05) depressed immediately following HIE. Our data indicate that increases in EPOC or fat oxidation following HIE appear unlikely to contribute to the reported superior fat loss compared with END.
Exercise training reduces systemic and adipose tissue inflammation. However, these beneficial effects seem to be largely tied to reductions in adipose tissue mass. The purpose of the present study was to determine if exercise training confers a protective effect against an acute inflammatory challenge. We hypothesized that the induction of inflammatory markers, such as interleukin 6 (IL-6), suppressor of cytokine signaling 3 (SOCS3), and TNF-α by the beta-3 adrenergic agonist CL 316,243 would be reduced in adipose tissue from trained mice and this would be associated with reductions in transient receptor potential cation channel 4 (TRPV4), a protein recently shown to regulate the expression of proinflammatory cytokines. Exercise training (4 wk of treadmill running, 1 h/day, 5 days/wk) increased markers of skeletal muscle mitochondrial content and the induction of PPAR-gamma coactivator 1 alpha in epididymal adipose tissue. The mRNA expression of IL-6, SOCS3, and TNFα were not different in subcutaneous and epididymal adipose tissue from sedentary and trained mice; however, the CL 316,243-mediated induction of these genes was attenuated ∼50% in epididymal adipose tissue from trained mice as were increases in plasma IL-6. The effects of training were not explained by reductions in lipolytic responsiveness, but were associated with decreases in TRPV4 protein content. These results highlight a previously unappreciated anti-inflammatory effect of exercise training on adipose tissue immunometabolism and underscores the value of assessing adipose tissue inflammation in the presence of an inflammatory insult.
Since the serendipitous discovery of the first antipsychotic (AP) drug in the 1950's, APs remain the cornerstone of treatment for schizophrenia. A shift over the past two decades away from first generation, conventional APs to so-called "atypical" (or second/ third generation) APs parallels acknowledgment of serious metabolic side-effects. As will be reviewed, AP drugs and type 2 diabetes are now inextricably linked, likely contributing to the 2-3-fold increased risk of type 2 diabetes observed in schizophrenia. However, this association is not straightforward. Biological and lifestyle-related illness factors contribute to the association between type 2 diabetes and metabolic disease independent of antipsychotic treatment. In addition, APs have a well-established weight gain propensity which could also account for elevated risk of insulin resistance and type 2 diabetes. However, compelling preclinical and clinical evidence now suggests that these drugs can rapidly influence pathways of glucose metabolism independently of weight gain, and even in absence of psychiatric illness. The clinical relevance of studying "direct" effects of these drugs on glucose metabolism is underscored by the widespread use of these medications both on- and off- label for a growing number of mental illnesses, extending safety concerns beyond schizophrenia.
MacPherson RE, Castellani L, Beaudoin M, Wright DC. Evidence for fatty acids mediating CL 316,243-induced reductions in blood glucose in mice. Am J Physiol Endocrinol Metab 307: E563-E570, 2014. First published August 5, 2014; doi:10.1152 doi:10. /ajpendo.00287.2014, a  3-adrenergic agonist, was developed as an antiobesity and diabetes drug and causes rapid decreases in blood glucose levels in mice. The mechanisms mediating this effect have not been fully elucidated; thus, the purpose of the current study was to examine the role of fatty acids and interleukin-6, reputed mediators of insulin secretion, in this process. To address this question, we used physiological and pharmacological approaches in combination with knockout mouse models. CL 316,243 treatment in male C57BL6 mice increased plasma fatty acids, glycerol, interleukin-6, and insulin and reduced blood glucose concentrations 2 h following injections. The ability of CL 316,243 to increase insulin and fatty acids and reduce glucose was preserved in interleukin-6-deficient mice. CL 316,243-induced drops in blood glucose occurred in parallel with increases in circulating fatty acids but prior to increases in plasma interleukin-6. CL 316,243-mediated increases in plasma insulin levels and reductions in blood glucose were attenuated when mice were pretreated with the lipase inhibitor nicotinic acid or in whole body adipose tissue triglyceride lipase knockout mice. Collectively, our findings demonstrate an important role for fatty acids in mediating the effects of CL 316,243 in mice. Not only do our results provide new insight into the mechanisms of action of CL 316,243, but they also hint at an unappreciated aspect of adipose tissue -pancreas cross-talk.CL 316,243 (CL) IS A SPECIFIC  3 -adrenergic agonist originally developed as an antiobesity and antidiabetic drug (1). Treating obese, insulin-resistant rodents with this compound for several weeks leads to improvements in glucose homeostasis and insulin sensitivity (7,8,31) that are likely related to CLmediated decreases in food intake (7, 9), increases in energy expenditure (9), and subsequent reductions in adipose tissue mass (7,8,31). In contrast, in lean human subjects, CL treatment results in increases in insulin-mediated glucose disposal (36) independent of changes in body composition, suggesting a direct effect of this compound on insulin sensitivity. In addition to these longer-term effects, CL rapidly (i.e., within minutes) increases insulin secretion and reduces blood glucose levels in mice in vivo (9). The whole body deletion of  3 -adrenergic receptors abolishes CL-mediated reductions in blood glucose and this is prevented when  3 -adrenergic receptors are reintroduced into white and brown adipocytes (9). However, when  3 -adrenergic receptors are reintroduced into brown adipoyctes only, the glucose lowering effects of CL are not recovered (9), providing evidence that a factor secreted from white adipocytes mediates the effects of CL on insulin secretion and reductions in blood glucose. At th...
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