Chronic AMP-kinase activation with AICAR reduces adiposity by remodeling adipocyte metabolism and increasing leptin sensitivity

This study investigated the effect of chronic AMP-kinase (AMPK) activation with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) on white adipose tissue (WAT) metabolism and the implications for visceral (VC) and subcutaneous (SC) adiposity, whole body-energy homeostasis, and hypothalamic leptin sensitivity. Male Wistar rats received daily single intraperitoneal injections of either saline or AICAR (0.7g/kg body weight) for 4 and 8 weeks and were pair-fed throughout the study. AICAR-treated rats had reduced adiposity with increased mitochondrial density in VC and SC fat pads, which was accompanied by reduced circulating leptin and time-dependent and depot-specific regulation of AMPK phosphorylation and FA oxidation. Interestingly, the anorectic effect to exogenous leptin was more pronounced in AICAR-treated animals than controls. This corresponded to reductions in hypothalamic AMPK phosphorylation and suppressor of cytokine signaling 3 content, whereas signal transducer and activator of transcription 3 phosphorylation was either unchanged or increased at 4 and 8 weeks in AICAR-treated rats. Ambulatory activity and whole-body energy expenditure (EE) were also increased with AICAR treatment. Altogether, chronic AICAR-induced AMPK activation increased WAT oxidative machinery, whole-body EE, and hypothalamic leptin sensitivity. This led to significant reductions in VC and SC adiposity without inducing energy-sparing mechanisms that oppose long-term fat loss. This study investigated the effect of chronic AMP-kinase (AMPK) activation with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) on white adipose tissue (WAT) metabolism and the implications for visceral (VC) and subcutaneous (SC) adiposity, whole body-energy homeostasis, and hypothalamic leptin sensitivity. Male Wistar rats received daily single intraperitoneal injections of either saline or AICAR (0.7g/kg body weight) for 4 and 8 weeks and were pair-fed throughout the study. AICAR-treated rats had reduced adiposity with increased mitochondrial density in VC and SC fat pads, which was accompanied by reduced circulating leptin and time-dependent and depot-specific regulation of AMPK phosphorylation and FA oxidation. Interestingly, the anorectic effect to exogenous leptin was more pronounced in AICAR-treated animals than controls. This corresponded to reductions in hypothalamic AMPK phosphorylation and suppressor of cytokine signaling 3 content, whereas signal transducer and activator of transcription 3 phosphorylation was either unchanged or increased at 4 and 8 weeks in AICAR-treated rats. Ambulatory activity and whole-body energy expenditure (EE) were also increased with AICAR treatment. Altogether, chronic AICAR-induced AMPK activation increased WAT oxidative machinery, whole-body EE, and hypothalamic leptin sensitivity. This led to significant reductions in VC and SC adiposity without inducing energy-sparing mechanisms that oppose long-term fat loss. Successful treatment of obesity requires a continuous reduction in adiposity and maintenance of a healthy body weight. The conventional approaches used to achieve weight loss involve exercise and diet. However, as body fat is reduced through these approaches, energy-sparing mechanisms are activated and impose a major obstacle to long-term weight loss (1Rosenbaum M. Leibel R.L. The physiology of body weight regulation: relevance to the etiology of obesity in children.Pediatrics. 1998; 101: 525-539Crossref PubMed Google Scholar). Therefore, identifying strategies to overcome these energy-sparing mechanisms is crucial to improve the outcome of weight loss programs. One potential approach would be to remodel white adipose tissue (WAT) metabolism toward a highly metabolic brown adipose tissue (BAT) phenotype that shifts metabolism toward fat oxidation instead of storage independently of altering whole-body energy expenditure (EE) through physical activity (2Hoehn K.L. Turner N. Swarbrick M.M. Wilks D. Preston E. Phua Y. Joshi H. Furler S.M. Larance M. Hegarty B.D. et al.Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity.Cell Metab. 2010; 11: 70-76Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). The acquisition of a “brown-like” phenotype by white adipocytes requires a substantial increase in mitochondrial content and upregulation of the oxidative machinery in these cells. These functional changes could ultimately reduce fat storage and adipose tissue mass. In this context, one enzyme that is central to sense the energy state of the cell and regulate ATP production through FA oxidation is AMP-kinase (AMPK). In its activated state, AMPK shuts down anabolic pathways and promotes catabolism by regulating the activity of key enzymes of intermediary metabolism (3Hardie D.G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.Nat. Rev. Mol. Cell Biol. 2007; 8: 774-785Crossref PubMed Scopus (1784) Google Scholar). AMPK has also been shown to block adipocyte differentiation in the early stages by inhibiting clonal expansion, which is a critical step for adipogenesis to occur (4Habinowski S.A. Witters L.A. The effects of AICAR on adipocyte differentiation of 3T3–L1 cells.Biochem. Biophys. Res. Commun. 2001; 286: 852-856Crossref PubMed Scopus (187) Google Scholar, 5Zhou Y. Wang D. Zhu Q. Gao X. Yang S. Xu A. Wu D. Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3–L1 adipogenesis.Biol. Pharm. Bull. 2009; 32: 993-998Crossref PubMed Scopus (44) Google Scholar). Additionally, treatment of preadipocytes with pharmacological agents to activate AMPK prevents the expression of late adipogenic markers, fatty acid synthase, acetyl-CoA carboxylase (ACC), and transcription factors peroxisome proliferator-activated receptor (PPAR)γ1/2 and CCAAT-enhancer-binding protein (C/EBP)α which are required for the synthesis and storage of lipids in mature adipocytes (4Habinowski S.A. Witters L.A. The effects of AICAR on adipocyte differentiation of 3T3–L1 cells.Biochem. Biophys. Res. Commun. 2001; 286: 852-856Crossref PubMed Scopus (187) Google Scholar, 5Zhou Y. Wang D. Zhu Q. Gao X. Yang S. Xu A. Wu D. Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3–L1 adipogenesis.Biol. Pharm. Bull. 2009; 32: 993-998Crossref PubMed Scopus (44) Google Scholar). AMPK also phosphorylates and activates PPAR-γ coactivator-1α (PGC-1α) and promotes mitochondrial biogenesis in skeletal muscle (6Canto C. Gerhart-Hines Z. Feige J.N. Lagouge M. Noriega L. Milne J.C. Elliott P.J. Puigserver P. Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.Nature. 2009; 458: 1056-1060Crossref PubMed Scopus (2403) Google Scholar). We have recently demonstrated that prolonged (15 h) AICAR-induced AMPK activation increased mRNA expression of PPAR-γ and of its coactivator PGC-1α in isolated rat epididymal adipocytes (7Gaidhu M.P. Fediuc S. Anthony N.M. So M. Mirpourian M. Perry R.L. Ceddia R.B. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.J. Lipid Res. 2009; 50: 704-715Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). These cells also had ∼4-fold higher than control expression of carnitine palmitoyl transferase-1b, which was accompanied by a 2-fold increase in palmitate oxidation and by a marked reduction in lipogenesis (7Gaidhu M.P. Fediuc S. Anthony N.M. So M. Mirpourian M. Perry R.L. Ceddia R.B. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.J. Lipid Res. 2009; 50: 704-715Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Based on these observations, we hypothesized that chronic activation of AMPK in vivo could lead to a shift in WAT metabolism toward oxidation and lead to reduced adiposity. Additionally, the effects of chronic AMPK activation on remodeling WAT metabolism could potentially overcome the opposition to fat reduction triggered by the centrally-mediated activation of energy-sparing mechanisms as adiposity is reduced (8Gaidhu M.P. Ceddia R.B. The role of adenosine monophosphate kinase in remodeling white adipose tissue metabolism.Exerc. Sport Sci. Rev. 2011; 39: 102-108Crossref PubMed Scopus (21) Google Scholar). Even though alterations in fat mass with chronic in vivo AICAR treatment in rodents have been previously reported (9Buhl E.S. Jessen N. Pold R. Ledet T. Flyvbjerg A. Pedersen S.B. Pedersen O. Schmitz O. Lund S. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome.Diabetes. 2002; 51: 2199-2206Crossref PubMed Scopus (208) Google Scholar, 10Narkar V.A. Downes M. Yu R.T. Embler E. Wang Y.X. Banayo E. Mihaylova M.M. Nelson M.C. Zou Y. Juguilon H. et al.AMPK and are exercise Full Text Full Text PDF PubMed Scopus Google Scholar, M. of AMP-activated protein kinase mitochondrial enzymes in skeletal PubMed Scopus Google is these effects and functional alterations in WAT or through alterations in whole-body energy Therefore, this study was to the effects of chronic in vivo AICAR-induced AMPK activation on visceral (VC) and subcutaneous (SC) WAT as as on whole-body energy have demonstrated that major depot-specific with to metabolic and A. S. and of brown adipocytes in the and adipose Metab. 2010; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). a of this study was also to VC and SC fat would to chronic AICAR-induced AMPK activation with to oxidative alterations in fat mass also leptin expression and by the WAT and this a major role in the regulation of whole-body R.L. energy and the effects of J. PubMed Scopus Google we the of content of signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 were in the to leptin signaling in this as as the anorectic of AICAR-treated animals to exogenous leptin This is the study to that chronic pharmacological AMPK activation in rats WAT metabolism by inducing mitochondrial biogenesis and fat loss without inducing energy-sparing this effect to be at by increased hypothalamic leptin sensitivity. and acid were acid was was AICAR was rat leptin was A. at the and were Cell carboxylase was and protein was were of the Male rats were on a at and were a single daily intraperitoneal of either saline or AICAR body weight for 4 and 8 The was on in vivo rat that used and for chronic AICAR injections (7Gaidhu M.P. Fediuc S. Anthony N.M. So M. Mirpourian M. Perry R.L. Ceddia R.B. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.J. Lipid Res. 2009; 50: 704-715Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 10Narkar V.A. Downes M. Yu R.T. Embler E. Wang Y.X. Banayo E. Mihaylova M.M. Nelson M.C. Zou Y. Juguilon H. et al.AMPK and are exercise Full Text Full Text PDF PubMed Scopus Google Scholar, M. of AMP-activated protein kinase mitochondrial enzymes in skeletal PubMed Scopus Google Scholar). rats were pair-fed to the AICAR-treated to control for effects of by the treatment. animals were pair-fed to the of by the AICAR-treated animals the animals received of the in the and the to at to prolonged of blood were to daily injections the and the was for of The was used to in vivo as previously R.L. M.P. Perry R.L. Ceddia R.B. and without altering circulating and in the role of and whole-body fat 2010; PubMed Scopus Google Scholar). the production and is also with a of that in the and was by the by the were on a throughout the 8 were in the at the daily saline or AICAR The of in the was is the required for the rats to to the R.L. M.P. Perry R.L. Ceddia R.B. and without altering circulating and in the role of and whole-body fat 2010; PubMed Scopus Google Scholar). The rats were for a the and and received daily injections of either saline or AICAR for this treatment control animals were pair-fed as the of the was the at and the animals were at with either saline or were the of the this the animals were and AICAR leptin and with either saline or rat leptin We used this of leptin has been previously demonstrated to a significant reduction in 4 in rats weeks of exercise in rats prolonged in central leptin and J. 2009; PubMed Scopus Google Scholar). In to animals were in the for with to epididymal and were and to for metabolic of were of body weight. body mass was as weight with and fat R.L. M.P. Perry R.L. Ceddia R.B. and without altering circulating and in the role of and whole-body fat 2010; PubMed Scopus Google Scholar). the 4 and 8 treatment fat and were and adipocytes were isolated tissue as previously (7Gaidhu M.P. Fediuc S. Anthony N.M. So M. Mirpourian M. Perry R.L. Ceddia R.B. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.J. Lipid Res. 2009; 50: 704-715Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, M.P. Anthony N.M. P. Ceddia R.B. of and metabolism in visceral and subcutaneous adipocytes by role of and J. Cell 2010; PubMed Scopus Google Scholar). palmitate cells were in with of and of of palmitate was by of (7Gaidhu M.P. Fediuc S. Anthony N.M. So M. Mirpourian M. Perry R.L. Ceddia R.B. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.J. Lipid Res. 2009; 50: 704-715Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, M.P. Anthony N.M. P. Ceddia R.B. of and metabolism in visceral and subcutaneous adipocytes by role of and J. Cell 2010; PubMed Scopus Google Scholar). were and with in WAT were and by in the at were in and in a of and S. M.C. R. E. P. for the study of brown adipose tissue and white adipose Mol. Biol. 2001; Google Scholar). 3 were and with and to was as the adipocyte of adipocytes the were with a a were with a of tissue were animals and a of in at were in a of and for were and in S. M.C. R. E. P. for the study of brown adipose tissue and white adipose Mol. Biol. 2001; Google Scholar). were with with lead and with a The and were the to tissue at density was as of the of were and in the was the the and the body as and in and at The were in a and and and and were the and was used to protein by the were with to for and to were used in a of for was by and of reduction in with AICAR injections has been in in rodents R. M. S. protein of regulates brown adipocyte 2010; PubMed Scopus Google was on a daily in to control rats. with was reduced by and 4 and 8 in AICAR-treated rats. in body weight or were control and AICAR-treated animals at of WAT mass that and fat were reduced in AICAR-treated animals by and 4 weeks and by and 8 In and fat adipocyte was reduced by and at 4 and by and at was unchanged in fat 4 weeks of AICAR treatment was than 8 weeks of protein content and in WAT that AICAR treatment increase the of brown adipocytes the WAT of adipocyte in 4 and 8 animals in and epididymal fat were at and the of for The and to of protein content in epididymal and brown adipose tissue (BAT) at 4 and 8 weeks control and AICAR-treated animals are as and was used as the control for the and was used as a control for 4 or 8 are as of mitochondrial density and we and fat as for SC and VC 4 and 8 weeks of AICAR mitochondrial density in and WAT was increased by and and by and Additionally, that adipocytes rats with AICAR for 4 or 8 weeks had with more with adipocytes control animals AMPK phosphorylation increased in and fat 4 and 8 weeks of AICAR treatment. The pronounced increase in AMPK phosphorylation was in the fat AMPK content in fat was reduced in the AICAR at effect no at phosphorylation and protein content were reduced at 4 in and fat the effect of AICAR on this was at the 8 with increased content oxidation increased in and adipocytes by and 4 weeks of AICAR with no in cells 8 weeks of AICAR palmitate oxidation reduced by and in and of WAT 4 and 8 animals are in and were to the study and no the with to and activity that increased by at 4 and by at 8 the in AICAR-treated rats This was also accompanied by and in activity as with in weeks 4 and was the to in AICAR-treated control rats and to AICAR 4 and 8 weeks a shift toward fat oxidation in AICAR-treated in were control and AICAR-treated rats the However, the that the daily AICAR to was in control than AICAR-treated animals and 4 and 8 This the in which the control animals of the of the to a reduction in 4 and 8 weeks of AICAR treatment. were the for 4 and 8 weeks of treatment. and the for the and and were with control for are as weeks 4 and 8 of leptin in animals was than by and In the phosphorylation at was either unchanged or increased and AMPK phosphorylation was reduced 4 and 8 weeks of AICAR the content of these unchanged content was also reduced in the AICAR at 4 and 8 of hypothalamic 4 and 8 animals are in We that in the of leptin administration in of AICAR animals a reduction in 4 with control rats This that this anorectic effect in these with control rats 4 with a to leptin Interestingly, with AICAR and animals a significant reduction in of with animals with AICAR This to a reduction in with control animals with in were a in control and AICAR-treated rats without or with with with with and were on a daily with either saline or AICAR for rats were for to with either saline or leptin and was 4 and as a of to the anorectic effects of for as with with and in a were on a daily with either saline or AICAR for rats were for to with either saline or leptin and was 4 and as a of to the anorectic effects of for as we novel that chronic AICAR-induced AMPK activation promotes alterations in adipose tissue metabolism that to reduced VC and SC adiposity in rats. These effects were by increased mitochondrial density and by the of with more in the WAT of AICAR-treated This was also accompanied by time-dependent upregulation of FA oxidation in and in that VC fat metabolic in to chronic AMPK are in with that fat is more to and metabolic changes with and fat which have and to metabolic A. S. and of brown adipocytes in the and adipose Metab. 2010; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, AICAR treatment reduced and increased EE, these animals fat mass the 4 and 8 to control energy this could be to the anorectic effect of AICAR at the 8 reduction in with 4 weeks reduction in Additionally, the of oxidation at 8 weeks would also of content the Therefore, the increase in have been by the factors and could AICAR-treated animals fat mass the 4 and 8 of this study was that the of adipocytes to was increased and reduced 4 and 8 weeks of AICAR This the that mitochondrial density was at that the activity of the oxidative machinery was the of treatment. The mechanisms these are be at by the that the to AMPK activation in WAT were to shift toward oxidation of This is by that oxidation of and exogenous was increased whereas the of FA and lipogenesis were in isolated adipocytes prolonged AICAR (7Gaidhu M.P. Fediuc S. Anthony N.M. So M. Mirpourian M. Perry R.L. Ceddia R.B. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL.J. Lipid Res. 2009; 50: 704-715Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). AMPK phosphorylation with of protein is with upregulation of FA oxidation 4 weeks of AICAR treatment. However, FA oxidation was reduced at 8 increased mitochondrial content in VC and SC adipocytes AICAR-treated rats. The reduction in FA oxidation could to the increased for the of FA to skeletal In skeletal have been previously demonstrated to increase to fat chronic AICAR-induced AMPK activation kinase activation with AICAR fatty acid and oxidation in rat PubMed Scopus Google Scholar, D.G. AMP-activated protein kinase, fatty acid and in rat J. PubMed Google Scholar). Therefore, the reduction in FA oxidation with the increased for FA in AICAR-treated rats. with AICAR was increased in fat at 4 and 8 weeks of alterations in protein AICAR treatment phosphorylation of as as this enzyme is a of However, the in content at 4 weeks in AICAR-treated animals would as a for phosphorylation of this In has been demonstrated in adipocytes that the content activity of are in cells with AMPK with adipogenic required for differentiation of preadipocytes mature fat cells (4Habinowski S.A. Witters L.A. The effects of AICAR on adipocyte differentiation of 3T3–L1 cells.Biochem. Biophys. Res. Commun. 2001; 286: 852-856Crossref PubMed Scopus (187) Google Scholar, 5Zhou Y. Wang D. Zhu Q. Gao X. Yang S. Xu A. Wu D. Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3–L1 adipogenesis.Biol. Pharm. Bull. 2009; 32: 993-998Crossref PubMed Scopus (44) Google Scholar). In animals AICAR treatment at to weeks in which have adipogenesis in preadipocytes in the Interestingly, at 8 was a in protein content with AICAR treatment phosphorylation of this enzyme in fat is that the of 8 weeks of treatment was of the metabolic in the time-dependent of FA oxidation of reduced adiposity. we also that phosphorylation was marked in AMPK phosphorylation at 8 of AICAR treatment. This that mechanisms activity as adipocyte content reduced with AICAR treatment. in with adipocytes has demonstrated that metabolic effects of AICAR in as FA oxidation and are by AMPK M.P. Fediuc S. Ceddia R.B. AMP-activated protein kinase phosphorylation and and fatty acid oxidation in isolated rat Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M.P. Perry R.L. Ceddia R.B. of signaling prevents AICAR-induced of phosphorylation and in rat 2010; PubMed Scopus (21) Google Scholar). However, treatment is in vivo and we that effects be in changes to whole-body and for the of in VC and SC fat demonstrated that brown adipogenesis by either of white brown adipocytes or of brown adipocyte WAT was with chronic AICAR-induced AMPK the of that AMPK is activated of ATP and to energy (3Hardie D.G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.Nat. Rev. Mol. Cell Biol. 2007; 8: 774-785Crossref PubMed Scopus (1784) Google is that content and activity was This would oxidation to be toward ATP synthesis instead of ultimately to cellular energy Therefore, that the increased oxidative machinery of adipocytes to chronic AICAR-induced AMPK activation white adipocytes to brown The of WAT in study is at with that have demonstrated this effect in to chronic AICAR treatment R. M. S. protein of regulates brown adipocyte 2010; PubMed Scopus Google Scholar). of AICAR treatment weeks 4 and 8 and of injections a could the to chronic AICAR treatment these The in whole-body 4 and 8 weeks of AICAR treatment to be by increased In this was increased by and 4 and 8 weeks of AICAR which is in with exercise V.A. Downes M. Yu R.T. Embler E. Wang Y.X. Banayo E. Mihaylova M.M. Nelson M.C. Zou Y. Juguilon H. et al.AMPK and are exercise Full Text Full Text PDF PubMed Scopus Google Scholar). oxidation by in skeletal muscle and to have to increased in AICAR-treated rats. This is on the that was increased in AICAR-treated rats the that was no in oxidation the pair-fed and AICAR-treated rats. have also shown that the in mitochondrial FA oxidation lead to whole-body (2Hoehn K.L. Turner N. Swarbrick M.M. Wilks D. Preston E. Phua Y. Joshi H. Furler S.M. Larance M. Hegarty B.D. et al.Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity.Cell Metab. 2010; 11: 70-76Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). has been demonstrated in rodents and that a reduction in fat mass is by activation of energy-sparing which resistance to continuous long-term reduction in adiposity R.L. energy and the effects of J. PubMed Scopus Google Scholar, M. R. D. A. L. S. D. L. E. Leibel R.L. leptin skeletal and to maintenance of reduced PubMed Scopus Google Scholar, M. S.B. Leibel R.L. leptin administration effects of on energy expenditure and circulating of Metab. 2002; PubMed Scopus Google Scholar). the whole-body these energy-sparing mechanisms could and potential effects by remodeling white adipocyte metabolism toward a more oxidative The activation of energy-sparing mechanisms of reduced adiposity has been to a in circulating leptin exogenous of this to this M. S.B. Leibel R.L. leptin administration effects of on energy expenditure and circulating of Metab. 2002; PubMed Scopus Google Scholar). In to its effects on energy M. Wang Y. E. et is required for leptin regulation of energy PubMed Scopus Google leptin to its receptor to the is and the to the expression of that and increase also promotes the expression of which as a of leptin Therefore, activation of AMPK in the and weight of this kinase by leptin these centrally-mediated effects on energy S. S. S. S. K.L. et activates hypothalamic acetyl-CoA carboxylase to Sci. 2007; PubMed Scopus Google Scholar, Y. T. N. A. J. P. et regulates by to and in the PubMed Scopus Google Scholar). Based on these observations, we hypothesized that energy-sparing mechanisms would be activated in AICAR-treated rats. This could occur by AICAR hypothalamic AMPK as have demonstrated that this the with P.J. T. J. T. E. of in PubMed Scopus Google Scholar). AICAR could lead to activation of energy-sparing mechanisms by circulating leptin as a of fat loss by prolonged AMPK activation in SC and VC fat that circulating leptin in AICAR-treated rats with pair-fed which was with the in adiposity the However, phosphorylation of hypothalamic AMPK was whereas phosphorylation was either the or increased in animals with 4 and 8 these effects were accompanied by marked reductions in the content of in the These that leptin in this tissue was increased with AICAR-induced AMPK In with this that with to the anorectic effects of AICAR-treated animals a to this with control This is by hypothalamic signaling that was reduced in AICAR-treated rats. Interestingly, leptin has been demonstrated to a major role in to the the of energy in the the central to regulate activity M. R. D. A. L. S. D. L. E. Leibel R.L. leptin skeletal and to maintenance of reduced PubMed Scopus Google Scholar, and mechanisms of activity and potential on 2007; PubMed Scopus Google Scholar, R. M. R. D. P. H. M. P. R. et a novel hypothalamic with is by energy PubMed Scopus Google Scholar). Therefore, the in activity and in this study could also be to central leptin sensitivity. are required to of AICAR on hypothalamic in the control of and energy Altogether, novel that significant reductions in adiposity be through pharmacological AMPK Based on this approach WAT to of brown adipocyte the oxidative machinery in white adipocytes and remodeling of WAT metabolism toward a the effects of chronic AICAR-induced AMPK activation increased hypothalamic leptin and the centrally-mediated that oppose long-term weight loss. The the of for in with acetyl-CoA carboxylase 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside AMP-kinase brown adipose tissue body weight energy expenditure epididymal intraperitoneal body mass peroxisome proliferator-activated receptor coactivator-1α peroxisome proliferator-activated receptor subcutaneous suppressor of cytokine signaling 3 signal transducer and activator of transcription 3 protein visceral white adipose tissue

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.