PURPOSE: Fatty acid esters of hydroxy fatty acids (FAHFAs) are a large family of endogenous bioactive lipids. To date, most of the studied FAHFAs are branched regioisomers of Palmitic Acid Hydroxyl Stearic Acid (PAHSA) that were reported to possess anti-diabetic and anti-inflammatory activity in humans and rodents. Recently, we have demonstrated that 9-PAHPA or 9-OAHPA intake increased basal metabolism and enhanced insulin sensitivity in healthy control diet-fed mice but induced liver damage in some mice. The present work aims to explore whether a long-term intake of 9-PAHPA or 9-OAHPA may have similar effects in obesogenic diet-fed mice. METHODS: C57Bl6 mice were fed with a control or high fat-high sugar (HFHS) diets for 12 weeks. The HFHS diet was supplemented or not with 9-PAHPA or 9-OAHPA. Whole-body metabolism was explored. Glucose and lipid metabolism as well as mitochondrial activity and oxidative stress status were analyzed. RESULTS: As expected, the intake of HFHS diet led to obesity and lower insulin sensitivity with minor effects on liver parameters. The long-term intake of 9-PAHPA or 9-OAHPA modulated favorably the basal metabolism and improved insulin sensitivity as measured by insulin tolerance test. On the contrary to what we have reported previously in healthy mice, no marked effect for these FAHFAs was observed on liver metabolism of obese diabetic mice. CONCLUSION: This study indicates that both 9-PAHPA and 9-OAHPA may have interesting insulin-sensitizing effects in obese mice with lower insulin sensitivity.

Aix Marseille Univ INSERM INRAE C2VN Marseille France

Department of Metabolism of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

DMEM INRAE Univ Montpellier Montpellier France

INSERM U1194 Network of Experimental Histology BioCampus CNRS UMS3426 Montpellier France

Institut Des Biomolécules Max Mousseron Université de Montpellier CNRS ENSCM Montpellier France

LNC UMR1231 INSERM Univ Bourgogne Franche Comté Agrosup Dijon LipSTIC LabEx Dijon France

Zobrazit více v PubMed

Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384(9945):766–781. https://doi.org/10.1016/S0140-6736(14)60460-8 PubMed DOI PMC

Alberti KG, Zimmet P, Shaw J, Group IDFETFC (2005) The metabolic syndrome–a new worldwide definition. Lancet 366(9491):1059–1062. https://doi.org/10.1016/S0140-6736(05)67402-8 DOI

Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R, Committee IDFDA (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 157:107843. https://doi.org/10.1016/j.diabres.2019.107843 PubMed DOI

Williams R, Karuranga S, Malanda B, Saeedi P, Basit A, Besancon S, Bommer C, Esteghamati A, Ogurtsova K, Zhang P, Colagiuri S (2020) Global and regional estimates and projections of diabetes-related health expenditure: results from the International Diabetes Federation Diabetes Atlas, edition. Diabetes Res Clin Pract 162:108072. https://doi.org/10.1016/j.diabres.2020.108072 PubMed DOI

Kim KH, Lee MS (2018) Pathogenesis of nonalcoholic steatohepatitis and hormone-based therapeutic approaches. Front Endocrinol (Lausanne) 9:485. https://doi.org/10.3389/fendo.2018.00485 DOI

Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346(16):1221–1231. https://doi.org/10.1056/NEJMra011775 PubMed DOI

Yore MM, Syed I, Moraes-Vieira PM, Zhang T, Herman MA, Homan EA, Patel RT, Lee J, Chen S, Peroni OD, Dhaneshwar AS, Hammarstedt A, Smith U, McGraw TE, Saghatelian A, Kahn BB (2014) Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159(2):318–332. https://doi.org/10.1016/j.cell.2014.09.035 PubMed DOI PMC

Balas L, Feillet-Coudray C, Durand T (2018) Branched fatty acyl esters of hydroxyl fatty acids (FAHFAs), appealing beneficial endogenous fat against obesity and type-2 diabetes. Chemistry 24(38):9463–9476. https://doi.org/10.1002/chem.201800853 PubMed DOI

Kuda O, Brezinova M, Rombaldova M, Slavikova B, Posta M, Beier P, Janovska P, Veleba J, Kopecky J Jr, Kudova E, Pelikanova T, Kopecky J (2016) Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties. Diabetes 65(9):2580–2590. https://doi.org/10.2337/db16-0385 PubMed DOI

Bandak B, Yi L, Roper MG (2018) Microfluidic-enabled quantitative measurements of insulin release dynamics from single islets of Langerhans in response to 5-palmitic acid hydroxy stearic acid. Lab Chip 18(18):2873–2882. https://doi.org/10.1039/c8lc00624e PubMed DOI PMC

Benlebna M, Balas L, Bonafos B, Pessemesse L, Vigor C, Grober J, Bernex F, Fouret G, Paluchova V, Gaillet S, Landrier JF, Kuda O, Durand T, Coudray C, Casas F, Feillet-Coudray C (2020) Long-term high intake of 9-PAHPA or 9-OAHPA increases basal metabolism and insulin sensitivity but disrupts liver homeostasis in healthy mice. J Nutr Biochem 79:108361. https://doi.org/10.1016/j.jnutbio.2020.108361 PubMed DOI

Paluchova V, Oseeva M, Brezinova M, Cajka T, Bardova K, Adamcova K, Zacek P, Brejchova K, Balas L, Chodounska H, Kudova E, Schreiber R, Zechner R, Durand T, Rossmeisl M, Abumrad NA, Kopecky J, Kuda O (2020) Lipokine 5-PAHSA is regulated by adipose triglyceride lipase and primes adipocytes for de novo lipogenesis in mice. Diabetes 69(3):300–312. https://doi.org/10.2337/db19-0494 PubMed DOI PMC

Balas L, Bertrand-Michel J, Viars F, Faugere J, Lefort C, Caspar-Bauguil S, Langin D, Durand T (2016) Regiocontrolled syntheses of FAHFAs and LC-MS/MS differentiation of regioisomers. Org Biomol Chem 14(38):9012–9020. https://doi.org/10.1039/c6ob01597b PubMed DOI

Marvyn PM, Bradley RM, Mardian EB, Marks KA, Duncan RE (2016) Data on oxygen consumption rate, respiratory exchange ratio, and movement in C57BL/6J female mice on the third day of consuming a high-fat diet. Data Brief 7:472–475. https://doi.org/10.1016/j.dib.2016.02.066 PubMed DOI PMC

Coudray C, Fouret G, Lambert K, Ferreri C, Rieusset J, Blachnio-Zabielska A, Lecomte J, Ebabe Elle R, Badia E, Murphy MP, Feillet-Coudray C (2016) A mitochondrial-targeted ubiquinone modulates muscle lipid profile and improves mitochondrial respiration in obesogenic diet-fed rats. Br J Nutr 115(7):1155–1166. https://doi.org/10.1017/S0007114515005528 PubMed DOI

Standish RA, Cholongitas E, Dhillon A, Burroughs AK, Dhillon AP (2006) An appraisal of the histopathological assessment of liver fibrosis. Gut 55(4):569–578. https://doi.org/10.1136/gut.2005.084475 PubMed DOI PMC

Sunderman FW Jr, Marzouk A, Hopfer SM, Zaharia O, Reid MC (1985) Increased lipid peroxidation in tissues of nickel chloride-treated rats. Ann Clin Lab Sci 15(3):229–236 PubMed

Griffith OW (1980) Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal Biochem 106(1):207–212. https://doi.org/10.1016/0003-2697(80)90139-6 PubMed DOI

Faure P, Lafond J (1995) Measurement of plasma sulfhydryl and carbonyl groups as a possible indicator of protein oxidation. In: Favier A, Cadet J, Kalyanaraman B, Fontecave M, Pierre J (eds) Analysis of Free Radicals in Biological Systems. Birkhauser Verlag Basel, Switzerland, pp 237–248 DOI

Beers RF Jr, Sizer IW (1952) A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem 195(1):133–140 DOI

Flohe L, Gunzler WA (1984) Assays of glutathione peroxidase. Methods Enzymol 105:114–121. https://doi.org/10.1016/s0076-6879(84)05015-1 PubMed DOI

Marklund S (1976) Spectrophotometric study of spontaneous disproportionation of superoxide anion radical and sensitive direct assay for superoxide dismutase. J Biol Chem 251(23):7504–7507 DOI

Dupuy A, Le Faouder P, Vigor C, Oger C, Galano JM, Dray C, Lee JC, Valet P, Gladine C, Durand T, Bertrand-Michel J (2016) Simultaneous quantitative profiling of 20 isoprostanoids from omega-3 and omega-6 polyunsaturated fatty acids by LC-MS/MS in various biological samples. Anal Chim Acta 921:46–58. https://doi.org/10.1016/j.aca.2016.03.024 PubMed DOI PMC

Feillet-Coudray C, Sutra T, Fouret G, Ramos J, Wrutniak-Cabello C, Cabello G, Cristol JP, Coudray C (2009) Oxidative stress in rats fed a high-fat high-sucrose diet and preventive effect of polyphenols: involvement of mitochondrial and NAD(P)H oxidase systems. Free Radic Biol Med 46(5):624–632 DOI

Srere P (1969) Citrate synthase. Methods Enzymol 13:3–11 DOI

Janssen AJ, Trijbels FJ, Sengers RC, Smeitink JA, van den Heuvel LP, Wintjes LT, Stoltenborg-Hogenkamp BJ, Rodenburg RJ (2007) Spectrophotometric assay for complex I of the respiratory chain in tissue samples and cultured fibroblasts. Clin Chem 53(4):729–734. https://doi.org/10.1373/clinchem.2006.078873 PubMed DOI

Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228(1):35–51. https://doi.org/10.1016/0009-8981(94)90055-8 PubMed DOI PMC

Wharton D, Tzagoloff A (1967) Cytochrome oxidase from beef heart mitochondria. Methods Enzymol 10:245–250 DOI

Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108(3):457–465. https://doi.org/10.1172/JCI11294 PubMed DOI PMC

Rabasa-Lhoret R, Laville M (2001) How to measure insulin sensitivity in clinical practice? Diabetes Metab 27(2 Pt 2):201–208 PubMed

Levene AP, Kudo H, Armstrong MJ, Thursz MR, Gedroyc WM, Anstee QM, Goldin RD (2012) Quantifying hepatic steatosis—more than meets the eye. Histopathology 60(6):971–981. https://doi.org/10.1111/j.1365-2559.2012.04193.x PubMed DOI

Gerspach C, Imhasly S, Klingler R, Hilbe M, Hartnack S, Ruetten M (2017) Variation in fat content between liver lobes and comparison with histopathological scores in dairy cows with fatty liver. BMC Vet Res 13(1):98. https://doi.org/10.1186/s12917-017-1004-9 PubMed DOI PMC

Manne V, Handa P, Kowdley KV (2018) Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis 22(1):23–37. https://doi.org/10.1016/j.cld.2017.08.007 PubMed DOI

Ferramosca A, Conte A, Damiano F, Siculella L, Zara V (2014) Differential effects of high-carbohydrate and high-fat diets on hepatic lipogenesis in rats. Eur J Nutr 53(4):1103–1114. https://doi.org/10.1007/s00394-013-0613-8 PubMed DOI

Lim J, Park HS, Kim J, Jang YJ, Kim JH, Lee Y, Heo Y (2020) Depot-specific UCP1 expression in human white adipose tissue and its association with obesity-related markers. Int J Obes (Lond) 44(3):697–706. https://doi.org/10.1038/s41366-020-0528-4 DOI

Tan D, Ertunc ME, Konduri S, Zhang J, Pinto AM, Chu Q, Kahn BB, Siegel D, Saghatelian A (2019) Discovery of FAHFA-containing triacylglycerols and their metabolic regulation. J Am Chem Soc 141(22):8798–8806. https://doi.org/10.1021/jacs.9b00045 PubMed DOI PMC

Pflimlin E, Bielohuby M, Korn M, Breitschopf K, Lohn M, Wohlfart P, Konkar A, Podeschwa M, Barenz F, Pfenninger A, Schwahn U, Opatz T, Reimann M, Petry S, Tennagels N (2018) Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab 28(2):217–227.e213 DOI

Kuda O (2018) On the complexity of PAHSA research. Cell Metab 28(4):541–542. https://doi.org/10.1016/j.cmet.2018.09.006 PubMed DOI

Syed I, Lee J, Peroni OD, Yore MM, Moraes-Vieira PM, Santoro A, Wellenstein K, Smith U, McGraw TE, Saghatelian A, Kahn BB (2018) Methodological issues in studying PAHSA biology: masking PAHSA effects. Cell Metab 28(4):543–546. https://doi.org/10.1016/j.cmet.2018.09.007 PubMed DOI PMC

Kolar MJ, Konduri S, Chang T, Wang H, McNerlin C, Ohlsson L, Harrod M, Siegel D, Saghatelian A (2019) Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals. J Biol Chem 294(27):10698–10707. https://doi.org/10.1074/jbc.RA118.006956 PubMed DOI PMC

Burchfield JG, Kebede MA, Meoli CC, Stockli J, Whitworth PT, Wright AL, Hoffman NJ, Minard AY, Ma X, Krycer JR, Nelson ME, Tan SX, Yau B, Thomas KC, Wee NKY, Khor EC, Enriquez RF, Vissel B, Biden TJ, Baldock PA, Hoehn KL, Cantley J, Cooney GJ, James DE, Fazakerley DJ (2018) High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice. J Biol Chem 293(15):5731–5745. https://doi.org/10.1074/jbc.RA117.000808 PubMed DOI PMC

Schneider K, Valdez J, Nguyen J, Vawter M, Galke B, Kurtz TW, Chan JY (2016) Increased energy expenditure, Ucp1 expression, and resistance to diet-induced obesity in mice lacking nuclear factor-erythroid-2-related transcription factor-2 (Nrf2). J Biol Chem 291(14):7754–7766. https://doi.org/10.1074/jbc.M115.673756 PubMed DOI PMC

Zhou P, Santoro A, Peroni OD, Nelson AT, Saghatelian A, Siegel D, Kahn BB (2019) PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms. J Clin Invest 129(10):4138–4150. https://doi.org/10.1172/JCI127092 PubMed DOI PMC

Wang YM, Liu HX, Fang NY (2018) 9-PAHSA promotes browning of white fat via activating G-protein-coupled receptor 120 and inhibiting lipopolysaccharide / NF-kappa B pathway. Biochem Biophys Res Commun 506(1):153–160. https://doi.org/10.1016/j.bbrc.2018.09.050 PubMed DOI

Zou T, Wang B, Yang Q, de Avila JM, Zhu MJ, You J, Chen D, Du M (2018) Raspberry promotes brown and beige adipocyte development in mice fed high-fat diet through activation of AMP-activated protein kinase (AMPK) alpha1. J Nutr Biochem 55:157–164. https://doi.org/10.1016/j.jnutbio.2018.02.005 PubMed DOI PMC

Ishibashi J, Seale P (2015) Functions of Prdm16 in thermogenic fat cells. Temperature (Austin) 2(1):65–72. https://doi.org/10.4161/23328940.2014.974444 DOI

Fernandes-Santos C, Carneiro RE, de Souza ML, Aguila MB, Mandarim-de-Lacerda CA (2009) Pan-PPAR agonist beneficial effects in overweight mice fed a high-fat high-sucrose diet. Nutrition 25(7–8):818–827. https://doi.org/10.1016/j.nut.2008.12.010 PubMed DOI

Syed I, Lee J, Moraes-Vieira PM, Donaldson CJ, Sontheimer A, Aryal P, Wellenstein K, Kolar MJ, Nelson AT, Siegel D, Mokrosinski J, Farooqi IS, Zhao JJ, Yore MM, Peroni OD, Saghatelian A, Kahn BB (2018) Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab 27(2):419–427.e414. https://doi.org/10.1016/j.cmet.2018.01.001 PubMed DOI PMC

Moraes-Vieira PM, Saghatelian A, Kahn BB (2016) GLUT4 expression in adipocytes regulates de novo lipogenesis and levels of a novel class of lipids with antidiabetic and anti-inflammatory effects. Diabetes 65(7):1808–1815. https://doi.org/10.2337/db16-0221 PubMed DOI PMC

Fujii H, Kawada N (2012) Inflammation and fibrogenesis in steatohepatitis. J Gastroenterol 47(3):215–225. https://doi.org/10.1007/s00535-012-0527-x PubMed DOI

Masarone M, Rosato V, Dallio M, Gravina AG, Aglitti A, Loguercio C, Federico A, Persico M (2018) Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longev 2018:9547613. https://doi.org/10.1155/2018/9547613 PubMed DOI PMC

Clapper JR, Hendricks MD, Gu G, Wittmer C, Dolman CS, Herich J, Athanacio J, Villescaz C, Ghosh SS, Heilig JS, Lowe C, Roth JD (2013) Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment. Am J Physiol Gastrointest Liver Physiol 305(7):G483–495. https://doi.org/10.1152/ajpgi.00079.2013 PubMed DOI

Wang YM, Liu HX, Fang NY (2018) High glucose concentration impairs 5-PAHSA activity by inhibiting AMP-activated protein kinase activation and promoting nuclear factor-kappa-B-mediated inflammation. Front Pharmacol 9:1491. https://doi.org/10.3389/fphar.2018.01491 PubMed DOI