Intestinal monocarboxylate transporter 1 mediates lactate transport in the gut and regulates metabolic homeostasis of mouse in a sex-dimorphic pattern

Abstract

The monocarboxylate transporter 1 (MCT1), encoded by gene Slc16a1, is a proton-coupled transporter for lactate and other monocarboxylates. MCT1-mediated lactate transport was recently found to regulate various biological functions. However, how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear. In this study, we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium (Slc16a1^IKO mice) and investigated the functions of MCT1 in the gut. When fed a high-fat diet, Slc16a1^IKO male mice had improvement in glucose tolerance and insulin sensitivity, while Slc16a1^IKO female mice only had increased adiposity. Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways, together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha (TNFα) and C–C motif chemokine ligand 2 (CCL2). Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro. The number of intestinal macrophages was reduced in Slc16a1^IKO male mice in vivo. Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine. In addition, treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1^IKO and wild-type mice. Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein. The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota. In conclusion, our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.

Keywords

MCT1 / intestine / lactate / short-chain fatty acids / insulin resistance / obesity

References

[1] Felmlee MA , Jones RS , Rodriguez-Cruz V et al. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease. Pharmacol Rev 2020; 72: 466- 85.

[2] Halestrap AP . The SLC16 gene family—structure, role and regulation in health and disease. Mol Aspects Med 2013; 34: 337- 49.

[3] Kim CM , Goldstein JL , Brown MS . cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function. J Biol Chem 1992; 267: 23113- 21.

[4] Garcia CK , Goldstein JL , Pathak RK et al. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 1994; 76: 865- 73.

[5] Meredith D , Christian HC . The SLC16 monocaboxylate transporter family. Xenobiotica 2008; 38: 1072- 106.

[6] Brooks GA . Intra- and extra-cellular lactate shuttles. Med Sci Sports Exerc 2000; 32: 790- 9.

[7] Sivaprakasam S , Bhutia YD , Yang S et al. Short-chain fatty acid transporters: role in colonic homeostasis. Compr Physiol 2017; 8: 299- 314.

[8] Payen VL , Mina E , Van Hee VF et al. Monocarboxylate transporters in cancer. Mol Metab 2020; 33: 48- 66.

[9] Halestrap AP . The monocarboxylate transporter family—structure and functional characterization. IUBMB Life 2012; 64: 1- 9.

[10] van Hasselt PM , Ferdinandusse S , Monroe GR et al. Monocarboxylate transporter 1 deficiency and ketone utilization. N Engl J Med 2014; 371: 1900- 7.

[11] Lengacher S , Nehiri-Sitayeb T , Steiner N et al. Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice. PLoS One 2013; 8: e82505.

[12] Chatel B , Bendahan D , Hourde C et al. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice. FASEB J 2017; 31: 2562- 75.

[13] Zhang J , Muri J , Fitzgerald G et al. Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization. Cell Metab 2020; 31: 1136- 53.e7.

[14] Jha MK , Passero JV , Rawat A et al. Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice. J Clin Invest 2021; 131: e141964.

[15] Lin Y , Bai M , Wang S et al. Lactate is a key mediator that links obesity to insulin resistance via modulating cytokine production from adipose tissue. Diabetes 2022; 71: 637- 52.

[16] Luo X , Li Z , Chen L et al. Monocarboxylate transporter 1 in the liver modulates high-fat diet-induced obesity and hepatic steatosis in mice. Metabolism 2023; 143: 155537.

[17] Van Rymenant E , Abranko L , Tumova S et al. Chronic exposure to short-chain fatty acids modulates transport and metabolism of microbiome-derived phenolics in human intestinal cells. J Nutr Biochem 2017; 39: 156- 68.

[18] Kayama H , Okumura R , Takeda K . Interaction between the microbiota, epithelia, and immune cells in the intestine. Annu Rev Immunol 2020; 38: 23- 48.

[19] Feng T , Zhao X , Gu P et al. Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2. Nat Commun 2022; 13: 5208.

[20] Curtis NJ , Mooney L , Hopcroft L et al. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity. Oncotarget 2017; 8: 69219- 36.

[21] Mauvais-Jarvis F , Clegg DJ , Hevener AL . The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 2013; 34: 309- 38.

[22] De Paoli M , Zakharia A , Werstuck GH . The role of estrogen in insulin resistance: a review of clinical and preclinical data. Am J Pathol 2021; 191: 1490- 8.

[23] Stubbins RE , Holcomb VB , Hong J et al. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr 2012; 51: 861- 70.

[24] Ribas V , Nguyen MT , Henstridge DC et al. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice. Am J Physiol Endocrinol Metab 2010; 298: E304- 19.

[25] Hui S , Ghergurovich JM , Morscher RJ et al. Glucose feeds the TCA cycle via circulating lactate. Nature 2017; 551: 115- 8.

[26] Wang L , Fouts DE , Starkel P et al. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosaassociated microbiota and preventing bacterial translocation. Cell Host Microbe 2016; 19: 227- 39.

[27] Luo C , Yu LT , Yang MQ et al. Recombinant Reg3β protein protects against streptozotocin-induced β-cell damage and diabetes. Sci Rep 2016; 6: 35640.

[28] Bajic D , Niemann A , Hillmer AK et al. Gut microbiota-derived propionate regulates the expression of Reg3 mucosal lectins and ameliorates experimental colitis in mice. J Crohns Colitis 2020; 14: 1462- 72.

[29] Link JC , Reue K . Genetic basis for sex differences in obesity and lipid metabolism. Annu Rev Nutr 2017; 37: 225- 45.

[30] Considine RV , Sinha MK , Heiman ML et al. Serum immunoreactiveleptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292- 5.

[31] Della Torre S , Mitro N , Meda C et al. Short-term fasting reveals amino acid metabolism as a major sex-discriminating factor in the liver. Cell Metab 2018; 28: 256- 67.e5.

[32] Richardson NE , Konon EN , Schuster HS et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice. Nat Aging 2021; 1: 73- 86.

[33] Liu M , Shen L , Yang Q et al. Sexual dimorphism in intestinal absorption and lymphatic transport of dietary lipids. J Physiol 2021; 599: 5015- 30.

[34] Gao A , Su J , Liu R et al. Sexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome. Nat Commun 2021; 12: 7080.

[35] Macotela Y , Boucher J , Tran TT et al. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes 2009; 58: 803- 12.

[36] Koh A , De Vadder F , Kovatcheva-Datchary P et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 2016; 165: 1332- 45.

[37] Turnbaugh PJ , Ley RE , Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444: 1027- 31.

[38] Flint HJ , Scott KP , Louis P et al. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012; 9: 577- 89.

[39] Park J , Goergen CJ , HogenEsch H et al. Chronically elevated levels of short-chain fatty acids induce T cell-mediated ureteritis and hydronephrosis. J Immunol 2016; 196: 2388- 400.

[40] Kim MH , Kang SG , Park JH et al. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 2013; 145: 396- 406.e10.

[41] Lee YS , Kim TY , Kim Y et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host Microbe 2018; 24: 833- 46.e6.

[42] Clemente JC , Ursell LK , Parfrey LW et al. The impact of the gut microbiota on human health: an integrative view. Cell 2012; 148: 1258- 70.

[43] Lynch SV , Pedersen O . The human intestinal microbiome in health and disease. N Engl J Med 2016; 375: 2369- 79.

[44] Amar J , Chabo C , Waget A et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med 2011; 3: 559- 72.

[45] Chang DH , Rhee MS , Ahn S et al. Faecalibaculum rodentium gen. nov., sp. nov., isolated from the faeces of a laboratory mouse. Antonie Van Leeuwenhoek 2015; 108: 1309- 18.

[46] Mathur H , Beresford TP , Cotter PD . Health benefits of lactic acid bacteria (LAB) fermentates. Nutrients 2020; 12: 1679.

[47] Barton LL , Fauque GD . Biochemistry, physiology and biotechnology of sulfate-reducing bacteria. Adv Appl Microbiol 2009; 68: 41- 98.

[48] Xiao S , Fei N , Pang X et al. A gut microbiota-targeted dietary intervention for amelioration of chronic inflammation underlying metabolic syndrome. FEMS Microbiol Ecol 2014; 87: 357- 67.

[49] Geurts L , Lazarevic V , Derrien M et al. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptinresistant mice: impact on apelin regulation in adipose tissue. Front Microbiol 2011; 2: 149.

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