Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice

Abstract

Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8 weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues. Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8 weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues. Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that induces insulin secretion, glucagon suppression, and appetite suppression through the signaling cascades of GLP-1 receptor (GLP-1R), which maintains glucose homeostasis and induces weight loss (1Gribble F.M. Reimann F. Metabolic messengers: glucagon-like peptide 1.Nat. Metab. 2021; 3: 142-148Crossref PubMed Scopus (61) Google Scholar, 2Drucker D.J. Mechanisms of action and therapeutic application of glucagon-like peptide-1.Cell Metab. 2018; 27: 740-756Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar, 3Madsbad S. Treatment of type 2 diabetes with incretin-based therapies.Lancet. 2009; 373: 438-439Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Holst J.J. Deacon C.F. Vilsboll T. Krarup T. Madsbad S. Glucagon-like peptide-1, glucose homeostasis and diabetes.Trends Mol. Med. 2008; 14: 161-168Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Owing to these beneficial actions, GLP-1 therapies have been applied in clinical development and are widely used for the treatment of type 2 diabetes mellitus and obesity (1Gribble F.M. Reimann F. Metabolic messengers: glucagon-like peptide 1.Nat. Metab. 2021; 3: 142-148Crossref PubMed Scopus (61) Google Scholar, 3Madsbad S. Treatment of type 2 diabetes with incretin-based therapies.Lancet. 2009; 373: 438-439Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 5Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat. Rev. Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (937) Google Scholar). Nevertheless, due to the short biological half-life of native GLP-1 (rapid elimination within 5 min) (5Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat. Rev. Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (937) Google Scholar, 6Hui H. Farilla L. Merkel P. Perfetti R. The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects.Eur. J. Endocrinol. 2002; 146: 863-869Crossref PubMed Scopus (111) Google Scholar), long-acting GLP-1R agonists have been developed, for example, liraglutide, dulaglutide, albiglutide, and the most recent semaglutide (7Nauck M.A. Quast D.R. Wefers J. Meier J.J. GLP-1 receptor agonists in the treatment of type 2 diabetes-state of the art.Mol. Metab. 2021; 46101102Crossref PubMed Scopus (387) Google Scholar). Among the currently available GLP-1R agonists, liraglutide has had the highest market penetration since its first approval by the Food and Drug Administration in 2010 (8Andersen A. Lund A. Knop F.K. Vilsboll T. Glucagon-like peptide 1 in health and disease.Nat. Rev. Endocrinol. 2018; 14: 390-403Crossref PubMed Scopus (262) Google Scholar, 9Parks M. Rosebraugh C. Weighing risks and benefits of liraglutide--the FDA's review of a new antidiabetic therapy.N. Engl. J. Med. 2010; 362: 774-777Crossref PubMed Scopus (230) Google Scholar). Part of the liraglutide molecule is hydrophobic because palmitate is attached at Lys26, allowing reversible binding to albumin, and this binding extends its biological half-life up to 13 h (10Malm-Erjefalt M. Bjornsdottir I. Vanggaard J. Helleberg H. Larsen U. Oosterhuis B. et al.Metabolism and excretion of the once-daily human glucagon-like peptide 1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase.Drug Metab. Dispos. 2010; 38: 1944-1953Crossref PubMed Scopus (144) Google Scholar, 11Larsen P.J. Fledelius C. Knudsen L.B. Tang-Christensen M. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats.Diabetes. 2001; 50: 2530-2539Crossref PubMed Scopus (224) Google Scholar, 12Knudsen L.B. Nielsen P.F. Huusfeldt P.O. Johansen N.L. Madsen K. Pedersen F.Z. et al.Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration.J. Med. Chem. 2000; 43: 1664-1669Crossref PubMed Scopus (576) Google Scholar). The clinical efficacy of liraglutide in the treatment of diabetes and obesity has been extensively documented (13Ostawal A. Mocevic E. Kragh N. Xu W. Clinical effectiveness of liraglutide in type 2 diabetes treatment in the real-world setting: a systematic literature review.Diabetes Ther. 2016; 7: 411-438Crossref PubMed Scopus (69) Google Scholar, 14Astrup A. Rossner S. Van Gaal L. Rissanen A. Niskanen L. Al Hakim M. et al.Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.Lancet. 2009; 374: 1606-1616Abstract Full Text Full Text PDF PubMed Scopus (863) Google Scholar, 15Davies M.J. Bergenstal R. Bode B. Kushner R.F. Lewin A. Skjoth T.V. et al.Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial.JAMA. 2015; 314: 687-699Crossref PubMed Scopus (623) Google Scholar, 16Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.New Engl. J. Med. 2015; 373: 11-22Crossref PubMed Scopus (1283) Google Scholar, 17Petit J.M. Cercueil J.P. Loffroy R. Denimal D. Bouillet B. Fourmont C. et al.Effect of liraglutide therapy on liver fat in patients with controlled type 2 diabetes: the Endocrinol. Metab. Google Scholar, S. et al.Effects of liraglutide on in patients with type 2 diabetes mellitus with or of or 2018; PubMed Scopus Google Scholar, C. et weight loss with liraglutide, or both Engl. J. Med. 2021; PubMed Scopus Google Scholar). The health benefits of liraglutide weight loss to appetite suppression, of fat and of glucose of and of X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.New Engl. J. Med. 2015; 373: 11-22Crossref PubMed Scopus (1283) Google Scholar, D. M. R. A. D. F. et and through PubMed Scopus Google Scholar, A. J. J. M.A. et GLP-1 receptor weight PubMed Scopus Google Scholar, T. M. T. Krarup T. J.P. et a long-acting human glucagon-like peptide-1 analog, as and weight of in patients with type 2 PubMed Scopus Google Scholar). by and liraglutide therapy the of tissues D.J. Mechanisms of action and therapeutic application of glucagon-like peptide-1.Cell Metab. 2018; 27: 740-756Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar). liraglutide appetite by in the of the hypothalamus through which in A. J. J. M.A. et GLP-1 receptor weight PubMed Scopus Google Scholar). liraglutide glucose and insulin in the liver by the signaling which the of glucose 2 J. J. P. R. effects of GLP-1 and on and Endocrinol. 2018; PubMed Scopus Google Scholar). also insulin action and glucose in the skeletal muscle by the glucose of the signaling glucose of signaling in skeletal muscle Full Text Full Text PDF PubMed Scopus (27) Google Scholar). the metabolic changes induced by liraglutide as the of metabolic are is a to which has in and the of metabolic as diabetes and obesity S. metabolomic to the metabolic obesity and 2015; 38: PubMed Scopus (111) Google Scholar, applied to diabetes to 2009; PubMed Scopus Google Scholar, L. C. N. L. et of the in obesity is with health Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). also used to drug that therapeutic of in drug and Rev. Drug 2016; PubMed Scopus Google Scholar). of the effects of the and anti-obesity as and dipeptidyl has been in patients or in E. I. R. et and dipeptidyl the and plasma of J. Full Text Full Text PDF PubMed Scopus Google Scholar, X. Al M. A. A. H. M. et with insulin and type 2 diabetes Mol. Scopus Google Scholar, X. Al M. A. H. et metabolic changes in type 2 patients with Google Scholar, P. M. H. M. B. B. et on in mice with diet-induced obesity and type 2 diabetes the of and PubMed Scopus Google Scholar). recent study has the effects of liraglutide treatment in diet-induced obese liraglutide of and and of and M. H. M. B. L. B. et effects of liraglutide in mice with diet-induced obesity by Endocrinol. PubMed Scopus Google Scholar). Although has as and the of of is to the on which are in the and not changes in various tissues S. F. R. C. et human PubMed Scopus Google Scholar). the of tissues is for the metabolism at the of or clinical Here, we report a comprehensive metabolomic study to the metabolic effects of liraglutide in the hypothalamus, plasma, liver, and skeletal muscle of mice fed high-fat diet and The and metabolic by liraglutide in of mice also in comparison to in nonobese mice. Our metabolomic liraglutide to the therapeutic of GLP-1R the clinical efficacy of liraglutide and the of the effects on metabolic with metabolic as obesity and metabolic changes induced by liraglutide, mice fed a normal diet or for 8 and daily subcutaneous of to as or of liraglutide for to as has on and glucose in nonobese changes several and in mice A. D. S. A. R. P. et effects of liraglutide, and on and of in a of Scopus Google Scholar, J. A. P. Xu B. R. L. induces fat development and in diet induced obesity mice through signaling PubMed Scopus Google Scholar). We nonobese mice with as to as to the beneficial effects of liraglutide on obese and of metabolism in obese the the hypothalamus, plasma, liver, and skeletal muscle and and in a weight loss and in mice the of liraglutide on we fat and the by liraglutide in mice and to a to that of and in comparison with treatment of mice for but not in comparison with these that liraglutide obese in mice. changes in metabolism induced by liraglutide in mice to we and and in in the hypothalamus, in plasma, in liver, and in skeletal revealed the effects of and liraglutide on the The metabolomic and not among the and a the a in Among these showed a in to or liraglutide changes in the and metabolic by or liraglutide, liraglutide and liraglutide the comparison in also showed a the comparison We the on which the of to the and the of the with and are through the changes and and in the plasma, liver, and skeletal muscle and 2 fatty and fatty in the hypothalamus and skeletal muscle and the metabolic by we a metabolite for or The the of metabolic in fatty acid and the the and metabolism in plasma and of the in the liver most of the are the of the or in the liver. the in the amino and the in the and Our that liraglutide the by but the and by and The of liraglutide and in liraglutide in plasma and in the hypothalamus and skeletal muscle in The in and metabolism of amino and the in the and amino The with and metabolic The hypothalamus is a and glucose metabolism metabolic as and amino which a in C. X. through of a 2009; PubMed Scopus Google Scholar, M. R. D. M.J. L. et fatty acid metabolism the action of Metab. 2008; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, D. of 2000; PubMed Scopus Google Scholar, N. of and glucose Metab. 2021; 3: PubMed Scopus Google Scholar). Although liraglutide appetite by GLP-1R in in the hypothalamus A. J. J. M.A. et GLP-1 receptor weight PubMed Scopus Google Scholar, of liraglutide in of obese 2016; PubMed Scopus Google Scholar, L. S. J. et and effects of liraglutide on and for and glucose Metab. PubMed Scopus Google Scholar), the metabolic changes by liraglutide in the hypothalamus are Our revealed that the among the but not in Among showed among the in by in and the of fatty acid and which by liraglutide also the of comparison and and are of fatty acid in which fatty the as and also and but liraglutide these amino in liraglutide to both and and the metabolic by or liraglutide, we metabolite for in and metabolic to acid and fatty acid which fatty acid in and liraglutide to fatty acid in the hypothalamus the or of metabolite by or liraglutide, we the of Among the that showed in the plasma of the of fatty and of amino in to of fatty and amino in of in to but of in liraglutide liraglutide fatty and amino that by in the is widely used in clinical and biological on metabolic K. Rev. PubMed Scopus Google Scholar). The not among the in or in Among showed among the showed and but liraglutide the of or amino amino and the and which by by liraglutide to liraglutide and also the of acid and to liraglutide the of these both of and liraglutide acid and to in and to to metabolic that among the amino acid liraglutide most of the metabolic by for amino and and metabolism in the plasma of mice Among the that showed in the plasma of the of amino of and of fatty in to of amino of and of fatty in liraglutide to The and in to and in liraglutide to these that liraglutide the plasma metabolism of amino fatty and that by in the liver showed that the of and liraglutide in but not in Among showed among the showed and fatty as and liraglutide fatty and in comparison with liraglutide and and also and these amino by and by and by liraglutide as and acid in liraglutide to and in and liraglutide to carbohydrate of as acid and of the acid as and and in the liraglutide of these to liraglutide and and by and by liraglutide to to most liver metabolic amino acid and carbohydrate not which in both and liraglutide to with liraglutide which by metabolic by liraglutide Among the that showed in the liver of the of amino and of in to of amino and of in of fatty in to but of fatty in or and in to both of by and in to and by liraglutide liraglutide amino fatty and by in the liver. in the skeletal muscle showed that the of and liraglutide in but in Among showed among the showed and fatty as and liraglutide of fatty amino acid and and liraglutide these amino which by by which by by liraglutide and in liraglutide to and liraglutide of and acid of and but amino in liraglutide to the skeletal with fatty that are the of of fatty fatty with and and fatty acid and in to the these metabolic in liraglutide to liraglutide which by and amino as and which not by Among the that showed in the skeletal muscle of the of fatty and of and of amino in to of fatty but of and of amino in or and in to and by liraglutide liraglutide fatty by in the skeletal muscle and amino acid and carbohydrate the metabolic and among we in the hypothalamus, plasma, liver, and skeletal muscle of tissues showed 1 the hypothalamus, plasma, the liver, and skeletal tissues and plasma had high with 2 5 plasma and the liver, that plasma and liver with of plasma The intertissue showed that liraglutide and muscle with of but not The showed that liraglutide with liraglutide showed with had the that liraglutide rewired metabolic and within the biological the beneficial effects of liraglutide on the of metabolism in obese we in mice with in nonobese mice induced changes in metabolism to that in nonobese liraglutide in diverse tissues and plasma of mice. We the and metabolic by liraglutide in mice to the in nonobese mice and the hypothalamus, and metabolism and by liraglutide in mice to in nonobese mice and the plasma, amino and had the of by liraglutide to tissues. amino acid metabolism and and carbohydrate metabolism acid and with the of metabolic and acid metabolism and by liraglutide and the metabolic of the liver, metabolism and fatty and by liraglutide and to tissues or plasma, skeletal muscle had the of fatty by liraglutide, the as of fatty fatty acid and acid metabolism and liraglutide metabolic and metabolic in mice in a which to the of a nonobese the beneficial effects of liraglutide in metabolism in diverse tissues and metabolic have been used in clinical and drug have been in tissues through S. metabolomic to the metabolic obesity and 2015; 38: PubMed Scopus (111) Google Scholar). the efficacy of liraglutide in and with diabetes or metabolomic study on the effects of liraglutide in tissues is study that used of the of mice has in and and in and M. H. M. B. L. B. et effects of liraglutide in mice with diet-induced obesity by Endocrinol. PubMed Scopus Google Scholar). Here, we used comprehensive that of and or to by liraglutide in the hypothalamus, plasma, liver, and skeletal muscle in mice. We the metabolic profiles of mice with of nonobese and obese mice to changes in and metabolomic among tissues. remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. fatty as and to and in the hypothalamus, and and glucose homeostasis C.F. W. J.P. S. et acid insulin by in 2009; PubMed Scopus Google Scholar, M. A. E. et to insulin and insulin PubMed Scopus Google Scholar). the and fatty as and homeostasis S. K. D. L. administration of acid glucose and 2002; PubMed Scopus Google Scholar, A. R. S. J. L. et of fatty is for glucose Med. PubMed Scopus Google Scholar, A. of acid on glucose insulin and Drug PubMed Scopus Google Scholar). Our showed that and not by liraglutide, but acid and fatty by liraglutide in the hypothalamus of obese mice to nonobese mice. The of acid by liraglutide may in changes in and glucose homeostasis induced by the skeletal liraglutide the of fatty to of fatty which due to an in are with a report that liraglutide in the skeletal muscle of L. C. M. C. X. B. et of a glucagon-like peptide-1 receptor in fat Endocrinol. PubMed Scopus Google Scholar). The of amino and in the plasma are well as metabolic for diabetes and obesity J. M.J. et al.A amino metabolic that obese and and to insulin Metab. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). amino the signaling in which insulin J. M. J. D. X. et insulin of of receptor through the of in diabetes in Chem. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, S. X. M. X. S. metabolic and of amino a 8: PubMed Scopus Google Scholar). Our showed that plasma amino by by on the metabolic profiles of or amino which used as for the acid and or a of the of amino in the liraglutide liver or in patients with fatty liver by which and fatty acid M.A. in fatty liver randomized controlled PubMed Scopus Google Scholar). metabolism as and are in mice S. I. S. et metabolic in mice to high fat diet induced weight an of PubMed Scopus Google and are by liraglutide M. H. M. B. L. B. et effects of liraglutide in mice with diet-induced obesity by Endocrinol. PubMed Scopus Google Scholar). We an in the of by in the liver and a by is to and through the and these are in the The metabolism of high of and acid in the J. PubMed Scopus Google Scholar). the of may on and tissues by in the of for the of liver by liraglutide M. H. M. B. L. B. et effects of liraglutide in mice with diet-induced obesity by Endocrinol. PubMed Scopus Google Scholar). in the liver which in the liver and excretion the a of liver a study of excretion in PubMed Scopus Google Scholar). the found that in the liver has beneficial as by the of and W. J. J. The beneficial effects of in metabolic 2016; 7: PubMed Google Scholar, W. The beneficial effects of in fatty liver 2021; Scopus Google Scholar, S. K. N. M. T. diabetes by glucose metabolism and in PubMed Scopus Google Scholar). Our showed that by in the liver by is that liraglutide induced changes in in the and liver, which is of a beneficial of liraglutide in the liver. and muscle metabolic in that liraglutide had the most on in the which the tissues, the high of in the liver and skeletal showed that metabolic profiles of liraglutide of but not of due to the that liraglutide does not the obese to a nonobese but the C. et weight loss with liraglutide, or both Engl. J. Med. 2021; PubMed Scopus Google Scholar, J. J. D. X. et effects of and in with GLP-1R agonists in Med. 2018; PubMed Scopus Google Scholar, S. J. N. D. R. et of to the of by GLP-1 receptor in 2015; PubMed Scopus Google Scholar). on and intertissue metabolic which the and of and among intertissue metabolic are for of and treatment to in in and weight loss in study and D. M. R. A. D. F. et and through PubMed Scopus Google Scholar, A. J. J. M.A. et GLP-1 receptor weight PubMed Scopus Google Scholar, J. A. P. Xu B. R. L. induces fat development and in diet induced obesity mice through signaling PubMed Scopus Google Scholar). metabolomic on a a or metabolomic in the and liver D. B. et of the hypothalamus of mice PubMed Scopus Google Scholar, H. T. M. of human new PubMed Scopus Google Scholar, J. of on metabolism in PubMed Scopus Google Scholar, D. J. S. H. et of changes in the of Metab. PubMed Scopus Google Scholar, A. T. N.L. F. et the metabolic benefits of short of 2021; PubMed Scopus Google Scholar, T. E. J.M. B. S. et al.A metabolomic of Endocrinol. Metab. PubMed Scopus Google Scholar, C. R. X. M. et to PubMed Google Scholar). these or a in the and liver of both and mice D. B. et of the hypothalamus of mice PubMed Scopus Google Scholar, H. T. M. of human new PubMed Scopus Google Scholar, J. of on metabolism in PubMed Scopus Google Scholar, D. J. S. H. et of changes in the of Metab. PubMed Scopus Google Scholar, A. T. N.L. F. et the metabolic benefits of short of 2021; PubMed Scopus Google Scholar). showed that liraglutide acid in the liver but not in the plasma of mice. a diet or a diet the of and in the and and in the liver both and D. B. et of the hypothalamus of mice PubMed Scopus Google Scholar, D. J. S. H. et of changes in the of Metab. PubMed Scopus Google Scholar, A. T. N.L. F. et the metabolic benefits of short of 2021; PubMed Scopus Google Scholar, T. E. J.M. B. S. et al.A metabolomic of Endocrinol. Metab. PubMed Scopus Google Scholar). study showed that liraglutide the of amino in the plasma and liver of that the metabolomic changes by liraglutide reflect by not only and weight loss but also beneficial effects of comprehensive metabolic with a liraglutide and various of diet high and of at the metabolite for the beneficial effects of liraglutide in diabetes to obesity. has the to of changes induced by drug which to and efficacy profiles Our study of the of liraglutide in mice metabolic alterations and within and across tissues. Metabolic alterations by liraglutide reflect its efficacy in which the to this the with the study may of the of liraglutide action and new new and for therapeutic intervention for diabetes and obesity. male mice at 8 of male mice in a in a at and controlled at had to and fed a diet or for 8 weeks. Food and weight the of the of and by the and at the of and in to as or to as mice daily for fed a normal diet only to as Administration the of the and and and a for and in The the as and The hypothalamus liver plasma and skeletal muscle of tissues and within in the of mice. The tissues in and in and at for The and in at for 1 to metabolite tissues in to with a of of and of for and and a a a and at for The and and to with of and through a of the with of in and of at for 1 in with and at for to of for at for the on for 5 and with of The of in an with an on an The as the the The at The at a of with or for 2 a of up to and at for or applied to and with used in and a H. S. M. et by with 2018; PubMed Scopus Google Scholar). The to to and by the the on an with an on a 2 at with acid in as and as B. The and the The as to 2 at 2 to 5 to 5 to to to the to The in with we the and and to and by the the the to and metabolic H. T. T. B. K. et for comprehensive 2015; PubMed Scopus Google with the to for of comprehensive of and or which is on J. L. M. et the and 2021; PubMed Scopus Google Scholar). or for in tissues or The mice in of the by The to by the by to the and by the of by with of or the with and or intertissue among we the and with of for both and and the at to and used to and the of as 2 or we an by the of to as and The as a by and metabolic only of metabolic as by with by at are within the and or are available the The that have of with the of this by the of and S. P. and K. S. P. and K. S. P. and K. S. P. and K. S. P. and S. S. P. and S. K. S. S. and K. with

Topics & Concepts