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Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg\/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.<\/jats:p>","DOI":"10.3390\/ijms23084082","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T13:39:51Z","timestamp":1649338791000},"page":"4082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7765-6727","authenticated-orcid":false,"given":"Renata","family":"Silv\u00e9rio","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"},{"name":"Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robson","family":"Barth","sequence":"additional","affiliation":[{"name":"Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"},{"name":"Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea S.","family":"Heimann","sequence":"additional","affiliation":[{"name":"Proteimax BioTechnology Israel LTD, 4 Duvdevan Street, Pardes Hana, Haifa 3708973, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Reckziegel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biomedical Science Institute, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9135-7184","authenticated-orcid":false,"given":"Gustavo J.","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"},{"name":"Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana Y.","family":"Romero-Zerbo","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, UGC Endocrinolog\u00eda y Nutrici\u00f3n Hospital Regional Universitario de M\u00e1laga, Universidad de M\u00e1laga, 29009 M\u00e1laga, Spain"},{"name":"Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-9691","authenticated-orcid":false,"given":"Francisco J.","family":"Berm\u00fadez-Silva","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, UGC Endocrinolog\u00eda y Nutrici\u00f3n Hospital Regional Universitario de M\u00e1laga, Universidad de M\u00e1laga, 29009 M\u00e1laga, Spain"},{"name":"Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8637-6097","authenticated-orcid":false,"given":"Alex","family":"Rafacho","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"},{"name":"Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"},{"name":"Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina (UFSC), Florian\u00f3polis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1651-9192","authenticated-orcid":false,"given":"Emer S.","family":"Ferro","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biomedical Science Institute, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1056\/NEJMra1514009","article-title":"Mechanisms, Pathophysiology, and Management of Obesity","volume":"376","author":"Heymsfield","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1111\/obr.12551","article-title":"Obesity: A chronic relapsing progressive disease process. A position statement of the World Obesity Federation","volume":"18","author":"Bray","year":"2017","journal-title":"Obes. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global epidemiology and pathogenesis","volume":"15","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Keaver, L., Webber, L., Dee, A., Shiely, F., Marsh, T., Balanda, K., and Perry, I. (2013). Application of the UK foresight obesity model in Ireland: The health and economic consequences of projected obesity trends in Ireland. PLoS ONE, 8.","DOI":"10.1371\/annotation\/3dd20b6b-2a94-4542-a058-2cc7effe881a"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s11892-017-0924-x","article-title":"Re-visiting the endocannabinoid system and its therapeutic potential in obesity and associated diseases","volume":"17","author":"Richey","year":"2017","journal-title":"Curr. Diabetes Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1080\/07853890510037419","article-title":"The endocannabinoid system and the treatment of obesity","volume":"37","author":"Pagotto","year":"2005","journal-title":"Ann. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/sj.ijo.0803539","article-title":"Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men","volume":"31","author":"Cote","year":"2007","journal-title":"Int. J. Obes."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.2337\/diabetes.54.10.2838","article-title":"Activation of the peripheral endocannabinoid system in human obesity","volume":"54","author":"Engeli","year":"2005","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13098-021-00647-2","article-title":"Diet-induced obesity in animal models: Points to consider and influence on metabolic markers","volume":"13","author":"Sediyama","year":"2021","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/sj.npp.1300370","article-title":"Blockade by the Cannabinoid CB1 Receptor Antagonist, Rimonabant (SR141716), of the Potentiation by Quinelorane of Food-Primed Reinstatement of Food-Seeking Behavior","volume":"29","author":"Duarte","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/sj.ijo.0802583","article-title":"CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity","volume":"28","author":"Delgorge","year":"2004","journal-title":"Int. J. Obes."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1172\/JCI17725","article-title":"The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis","volume":"112","author":"Cota","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1056\/NEJMoa044537","article-title":"Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia","volume":"353","author":"Golay","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1001\/jama.295.7.761","article-title":"Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: A randomized controlled trial","volume":"295","author":"Aronne","year":"2006","journal-title":"Jama"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1016\/S0140-6736(06)69571-8","article-title":"Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: A randomised controlled study","volume":"368","author":"Scheen","year":"2006","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/S0140-6736(05)66374-X","article-title":"Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study","volume":"365","author":"Rissanen","year":"2005","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1055\/s-2006-925401","article-title":"Cannabinoid receptor signaling directly inhibits thermogenesis and alters expression of adiponectin and visfatin","volume":"38","author":"Perwitz","year":"2006","journal-title":"Horm. Metab. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1016\/S0140-6736(07)61721-8","article-title":"Efficacy and safety of the weight-loss drug rimonabant: A meta-analysis of randomised trials","volume":"370","author":"Christensen","year":"2007","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1590\/S1516-44462009000200012","article-title":"The psychiatric side-effects of rimonabant","volume":"31","author":"Moreira","year":"2009","journal-title":"Braz. J. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.pbb.2010.03.012","article-title":"The endocannabinoid system, eating behavior and energy homeostasis: The end or a new beginning?","volume":"95","author":"Viveros","year":"2010","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14781","DOI":"10.1038\/s41598-017-13690-9","article-title":"A novel peptide that improves metabolic parameters without adverse central nervous system effects","volume":"7","author":"Reckziegel","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.2174\/1568026619666190708164841","article-title":"Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: Current approaches for therapeutics development","volume":"19","author":"Nguyen","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5361","DOI":"10.1096\/fj.13-247643","article-title":"Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity","volume":"28","author":"Boon","year":"2014","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14414","DOI":"10.1002\/anie.201807298","article-title":"Orally Active Peptides: Is There a Magic Bullet?","volume":"57","author":"Reichart","year":"2018","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.drudis.2021.01.020","article-title":"New perspectives in oral peptide delivery","volume":"26","author":"Zizzari","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.peptides.2004.10.026","article-title":"Antinociceptive action of hemopressin in experimental hyperalgesia","volume":"26","author":"Dale","year":"2005","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20588","DOI":"10.1073\/pnas.0706980105","article-title":"Hemopressin is an inverse agonist of CB1 cannabinoid receptors","volume":"104","author":"Heimann","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1111\/ijfs.14048","article-title":"Intestinal absorption of small peptides: A review","volume":"54","author":"Shen","year":"2019","journal-title":"Int. J. Food Sci. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108406","DOI":"10.1016\/j.neuropharm.2020.108406","article-title":"Hemopressin as a breakthrough for the cannabinoid field","volume":"183","author":"Heimann","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"134765","DOI":"10.1016\/j.neulet.2020.134765","article-title":"NFKF is a synthetic fragment derived from rat hemopressin that protects mice from neurodegeneration","volume":"721","author":"Heimann","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173636","DOI":"10.1016\/j.ejphar.2020.173636","article-title":"The potential anti-inflammatory and anti-nociceptive effects of rat hemopressin (PVNFKFLSH) in experimental arthritis","volume":"890","author":"Camargo","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"De Araujo, C.B., Heimann, A.S., Remer, R.A., Russo, L.C., Colquhoun, A., Forti, F.L., and Ferro, E.S. (2019). Intracellular Peptides in Cell Biology and Pharmacology. Biomolecules, 9.","DOI":"10.3390\/biom9040150"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.pbb.2014.11.013","article-title":"Anxiogenic-like effects induced by hemopressin in rats","volume":"129","author":"Sonego","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1213\/ANE.0b013e31824c4eeb","article-title":"The effects of peptide and lipid endocannabinoids on arthritic pain at the spinal level","volume":"114","author":"Petrovszki","year":"2012","journal-title":"Anesth. Analg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1590\/S0074-02762005000900017","article-title":"Hemopressin: A novel bioactive peptide derived from the alpha1-chain of hemoglobin","volume":"100","author":"Dale","year":"2005","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.neuropharm.2013.03.007","article-title":"Central functional response to the novel peptide cannabinoid, hemopressin","volume":"71","author":"Dodd","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7369","DOI":"10.1523\/JNEUROSCI.5455-09.2010","article-title":"The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice","volume":"30","author":"Dodd","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Silva, R.N.O., Llanos, R.P., Eichler, R.A.S., Oliveira, T.B., Gozzo, F.C., Festuccia, W.T., and Ferro, E.S. (2021). New Intracellular Peptide Derived from Hemoglobin Alpha Chain Induces Glucose Uptake and Reduces Blood Glycemia. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122175"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0742-8413(93)90047-O","article-title":"Oral administration of peptides derived from bonito bowels decreases blood pressure in spontaneously hypertensive rats by inhibiting angiotensin converting enzyme","volume":"104","author":"Hideaki","year":"1993","journal-title":"Comp. Biochem. Physiol. Part C: Comp. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41538-021-00108-0","article-title":"Oral intake of rice overexpressing ubiquitin ligase inhibitory pentapeptide prevents atrophy in denervated skeletal muscle","volume":"5","author":"Nakao","year":"2021","journal-title":"NPJ Sci. Food"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/MCO.0000000000000642","article-title":"Bioactive peptides derived from human milk proteins: An update","volume":"23","author":"Wada","year":"2020","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1021\/acs.jproteome.8b00604","article-title":"Peptidomics analysis of milk protein-derived peptides released over time in the preterm infant stomach","volume":"18","author":"Beverly","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Nielsen, S.D., Beverly, R.L., Underwood, M.A., and Dallas, D.C. (2018). Release of functional peptides from mother\u2019s milk and fortifier proteins in the premature infant stomach. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0208204"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fnut.2017.00054","article-title":"Peptides Released from Foremilk and Hindmilk Proteins by Breast Milk Proteases Are Highly Similar","volume":"4","author":"Nielsen","year":"2017","journal-title":"Front. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jnutbio.2013.10.012","article-title":"Bioactive peptides derived from human milk proteins\u2014Mechanisms of action","volume":"25","author":"Wada","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1113\/EP087317","article-title":"Decrement in resting and insulin-stimulated soleus muscle mitochondrial respiration is an early event in diet-induced obesity in mice","volume":"104","author":"Brunetta","year":"2019","journal-title":"Exp. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"103544","DOI":"10.1016\/j.jff.2019.103544","article-title":"Leucine increases muscle mitochondrial respiration and attenuates glucose intolerance in diet-induced obesity in Swiss mice","volume":"62","author":"Brunetta","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Parada, C.A., de Oliveira, I.P., Gewehr, M.C.F., Machado-Neto, J.A., Lima, K., Eichler, R.A.S., Lopes, L.R., Bechara, L.R.G., Ferreira, J.C.B., and Festuccia, W.T. (2022). Effect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP-FRB Interaction and Autophagy. Cells, 11.","DOI":"10.3390\/cells11030385"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.metabol.2007.12.004","article-title":"Dexamethasone treatment in vivo counteracts the functional pancreatic islet alterations caused by malnourishment in rats","volume":"57","author":"Giozzet","year":"2008","journal-title":"Metabolism"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Liang, W., Menke, A.L., Driessen, A., Koek, G.H., Lindeman, J.H., Stoop, R., Havekes, L.M., Kleemann, R., and van den Hoek, A.M. (2014). Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115922"},{"key":"ref_51","first-page":"972","article-title":"Disruption of glucose tolerance caused by glucocorticoid excess in rats is partially prevented, but not attenuated, by arjunolic acid","volume":"52","author":"Ferreira","year":"2014","journal-title":"Indian J. Exp. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Santos, N.B.D., Franco, R.D., Camarini, R., Munhoz, C.D., Eichler, R.A.S., Gewehr, M.C.F., Reckziegel, P., Llanos, R.P., Dale, C.S., and Silva, V. (2019). Thimet Oligopeptidase (EC 3.4.24.15) Key Functions Suggested by Knockout Mice Phenotype Characterization. Biomolecules, 9.","DOI":"10.3390\/biom9080382"},{"key":"ref_53","first-page":"257","article-title":"Mathematical contributions to the theory of evolution. II. Skew variation in homogeneous material","volume":"57","author":"Pearson","year":"1985","journal-title":"Proc. R. Soc. Lond."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.metabol.2015.11.008","article-title":"Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"65","author":"Brown","year":"2016","journal-title":"Metabolism"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.biochi.2017.01.007","article-title":"UCP1 in adipose tissues: Two steps to full browning","volume":"134","author":"Kalinovich","year":"2017","journal-title":"Biochimie"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4093\/dmj.2016.40.1.12","article-title":"Brown Fat and Browning for the Treatment of Obesity and Related Metabolic Disorders","volume":"40","author":"Kim","year":"2016","journal-title":"Diabetes Metab. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/978-1-61779-430-8_27","article-title":"A mouse model of diet-induced obesity and insulin resistance","volume":"821","author":"Wang","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1080\/21623945.2020.1870060","article-title":"Brown and beige adipose tissue: A novel therapeutic strategy for obesity and type 2 diabetes mellitus","volume":"10","author":"Cheng","year":"2021","journal-title":"Adipocyte"},{"key":"ref_59","first-page":"286","article-title":"The therapeutic potential of brown adipose tissue","volume":"2","author":"Stanford","year":"2013","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1097\/MCO.0000000000000063","article-title":"Brown fat fuel use and regulation of energy homeostasis","volume":"17","author":"Loyd","year":"2014","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nm.2297","article-title":"Brown adipose tissue activity controls triglyceride clearance","volume":"17","author":"Bartelt","year":"2011","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Luong, Q., Huang, J., and Lee, K.Y. (2019). Deciphering white adipose tissue heterogeneity. Biology, 8.","DOI":"10.3390\/biology8020023"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/21623945.2017.1319535","article-title":"Quantification of UCP1 function in human brown adipose tissue","volume":"6","author":"Porter","year":"2017","journal-title":"Adipocyte"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1194\/jlr.M052746","article-title":"Brown adipose tissue takes up plasma triglycerides mostly after lipolysis","volume":"56","author":"Khedoe","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.bbalip.2014.03.013","article-title":"Physiological regulation of lipoprotein lipase","volume":"1841","author":"Kersten","year":"2014","journal-title":"Biochim. Biophys. Acta-Mol. Cell Biol. Lipids"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"851","DOI":"10.5114\/aoms.2016.58928","article-title":"Obesity and inflammation: The linking mechanism and the complications","volume":"13","author":"Ellulu","year":"2017","journal-title":"Arch. Med. Sci"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"279","DOI":"10.4161\/gmic.19625","article-title":"Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity","volume":"3","author":"Cani","year":"2012","journal-title":"Gut Microbes"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/j.molmet.2017.08.011","article-title":"Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice","volume":"6","author":"Jourdan","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"549352","DOI":"10.1155\/2015\/549352","article-title":"Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice","volume":"2015","author":"Dinh","year":"2015","journal-title":"Sci. World J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41420-021-00711-w","article-title":"Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance","volume":"7","author":"Feng","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2014.12.017","article-title":"The mAb against adipocyte fatty acid-binding protein 2E4 attenuates the inflammation in the mouse model of high-fat diet-induced obesity via toll-like receptor 4 pathway","volume":"403","author":"Miao","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1096\/fj.201801152RR","article-title":"A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice","volume":"33","author":"Han","year":"2019","journal-title":"FASEB J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e21232","DOI":"10.1096\/fj.202001960R","article-title":"Peripheral CB1R as a modulator of metabolic inflammation","volume":"35","author":"Han","year":"2021","journal-title":"FASEB J."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Deveaux, V., Cadoudal, T., Ichigotani, Y., Teixeira-Clerc, F., Louvet, A., Manin, S., Nhieu, J.T.-V., Belot, M.P., Zimmer, A., and Even, P. (2009). Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005844"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.cmet.2007.11.013","article-title":"Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis","volume":"7","author":"Biddinger","year":"2008","journal-title":"Cell Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1172\/JCI200523057","article-title":"Endocannabinoid activation at hepatic CB 1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity","volume":"115","author":"DePetrillo","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1172\/JCI34827","article-title":"Hepatic CB 1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice","volume":"118","author":"Liu","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1111\/liv.14476","article-title":"Integration of miRNA-regulatory networks in hepatic stellate cells identifies TIMP3 as a key factor in chronic liver disease","volume":"40","author":"Azar","year":"2020","journal-title":"Liver Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"926","DOI":"10.2337\/db09-1482","article-title":"CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice","volume":"59","author":"Jourdan","year":"2010","journal-title":"Diabetes"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1194\/jlr.M019257","article-title":"Liver Patt1 deficiency protects male mice from age-associated but not high-fat diet-induced hepatic steatosis","volume":"53","author":"Liu","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1161\/ATVBAHA.108.176362","article-title":"Effect of rimonabant on the high-triglyceride\/low\u2013HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: The ADAGIO-Lipids trial","volume":"29","author":"Ross","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/hep.24733","article-title":"Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: Evidence from cultured explants","volume":"55","author":"Jourdan","year":"2012","journal-title":"Hepatology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.tox.2007.11.021","article-title":"The current state of serum biomarkers of hepatotoxicity","volume":"245","author":"Ozer","year":"2008","journal-title":"Toxicology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1194\/jlr.M054080","article-title":"ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content","volume":"56","author":"Camporez","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_85","first-page":"1","article-title":"Triglyceride Metabolism in the Liver","volume":"8","author":"Cohen","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/j.cell.2018.10.016","article-title":"Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation","volume":"175","author":"Li","year":"2018","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/s42255-021-00409-4","article-title":"Secretin activates brown fat and induces satiation","volume":"3","author":"Laurila","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1152\/physrev.00015.2003","article-title":"Brown adipose tissue: Function and physiological significance","volume":"84","author":"Cannon","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0165-6147(02)02072-2","article-title":"Mammalian peptide transporters as targets for drug delivery","volume":"23","author":"Daniel","year":"2002","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/jps.10303","article-title":"Current perspectives on established and putative mammalian oligopeptide transporters","volume":"92","author":"Knipp","year":"2003","journal-title":"J. Pharm. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1021\/mp8001655","article-title":"Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine","volume":"5","author":"Hu","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.coph.2013.08.004","article-title":"Drug transport via the intestinal peptide transporter PepT1","volume":"13","author":"Brandsch","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"De la Torre, B.G., and Albericio, F. (2020). Peptide Therapeutics 2.0, Multidisciplinary Digital Publishing Institute.","DOI":"10.3390\/molecules25102293"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"De la Torre, B.G., and Albericio, F. (2020). The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules. 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