Abstract
Overweight and obesity are characterized by excessive fat mass accumulation produced when energy intake exceeds energy expenditure. One plausible way to control energy expenditure is to modulate thermogenic pathways in white adipose tissue (WAT) and/or brown adipose tissue (BAT). Among the different environmental factors capable of influencing host metabolism and energy balance, the gut microbiota is now considered a key player. Following pioneering studies showing that mice lacking gut microbes (that is, germ-free mice) or depleted of their gut microbiota (that is, using antibiotics) developed less adipose tissue, numerous studies have investigated the complex interactions existing between gut bacteria, some of their membrane components (that is, lipopolysaccharides), and their metabolites (that is, short-chain fatty acids, endocannabinoids, bile acids, aryl hydrocarbon receptor ligands and tryptophan derivatives) as well as their contribution to the browning and/or beiging of WAT and changes in BAT activity. In this Review, we discuss the general physiology of both WAT and BAT. Subsequently, we introduce how gut bacteria and different microbiota-derived metabolites, their receptors and signalling pathways can regulate the development of adipose tissue and its metabolic capacities. Finally, we describe the key challenges in moving from bench to bedside by presenting specific key examples.
Key points
-
Approximately 40% of the global population is affected by overweight or obesity; novel treatments focusing on modulating thermogenic pathways in adipose tissue and altering gut microbiota are being explored.
-
Adipose tissues, categorized as white, brown and beige, have distinct roles in energy storage, thermogenesis and metabolism in the body.
-
Environmental factors substantially influence energy metabolism, with diet, exercise and sleep being primary contributors.
-
Gut bacteria are involved in bidirectional communication between the gut and adipose tissue, influencing energy metabolism, nutrient absorption, appetite and adipose tissue function.
-
Adipose tissue hosts its own distinct microbiota, which varies based on metabolic health and other factors; its understanding could offer novel insights.
-
Translating gut microbiota research from animal models to human applications faces methodological and biological challenges.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Valenzuela, P. L. et al. Obesity and the risk of cardiometabolic diseases. Nat. Rev. Cardiol. 20, 475–494 (2023).
Saha, A., Kolonin, M. G. & DiGiovanni, J. Obesity and prostate cancer — microenvironmental roles of adipose tissue. Nat. Rev. Urol. 20, 579–596 (2023).
de Vos, W. M., Tilg, H., Van Hul, M. & Cani, P. D. Gut microbiome and health: mechanistic insights. Gut 71, 1020–1032 (2022).
Van Hul, M. & Cani, P. D. The gut microbiota in obesity and weight management: microbes as friends or foe. Nat. Rev. Endocrinol. 19, 258–271 (2023).
Lafontan, M. Historical perspectives in fat cell biology: the fat cell as a model for the investigation of hormonal and metabolic pathways. Am. J. Physiol. Cell Physiol. 302, C327–C359 (2012).
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A. & Smith, U. Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Physiol. Rev. 98, 1911–1941 (2018).
White, U., Beyl, R. A. & Ravussin, E. A higher proportion of small adipocytes is associated with increased visceral and ectopic lipid accumulation during weight gain in response to overfeeding in men. Int. J. Obes. 46, 1560–1563 (2022).
White, U. & Ravussin, E. Dynamics of adipose tissue turnover in human metabolic health and disease. Diabetologia 62, 17–23 (2019).
Koenen, M., Hill, M. A., Cohen, P. & Sowers, J. R. Obesity, adipose tissue and vascular dysfunction. Circ. Res. 128, 951–968 (2021).
Longo, M. et al. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int. J. Mol. Sci. 20, 2358 (2019).
Kahn, C. R., Wang, G. & Lee, K. Y. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J. Clin. Invest. 129, 3990–4000 (2019).
Karpe, F. & Pinnick, K. E. Biology of upper-body and lower-body adipose tissue — link to whole-body phenotypes. Nat. Rev. Endocrinol. 11, 90–100 (2015).
Zhang, M., Hu, T., Zhang, S. & Zhou, L. Associations of different adipose tissue depots with insulin resistance: a systematic review and meta-analysis of observational studies. Sci. Rep. 5, 18495 (2015).
Tchkonia, T. et al. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 17, 644–656 (2013).
McLaughlin, T., Lamendola, C., Liu, A. & Abbasi, F. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J. Clin. Endocrinol. Metab. 96, E1756–1760 (2011).
Klein, S. et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N. Engl. J. Med. 350, 2549–2557 (2004).
Tran, T. T., Yamamoto, Y., Gesta, S. & Kahn, C. R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).
Cypess, A. M. Reassessing human adipose tissue. N. Engl. J. Med. 386, 768–779 (2022).
Luong, Q., Huang, J. & Lee, K. Y. Deciphering white adipose tissue heterogeneity. Biology 8, 23 (2019).
Iacobellis, G. Epicardial adipose tissue in contemporary cardiology. Nat. Rev. Cardiol. 19, 593–606 (2022).
Zhang, H. et al. Characteristics of mesenteric adipose tissue attached to different intestinal segments and their roles in immune regulation. Am. J. Physiol. Gastrointest. Liver Physiol. 322, G310–G326 (2022).
Wu, Z. et al. Mesenteric adipose tissue contributes to intestinal barrier integrity and protects against nonalcoholic fatty liver disease in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G659–G670 (2018).
Yu, Z., Wang, Y., Yu, Z., Lu, M. & Xu, B. Crosstalk between adipose tissue and the microbiota-gut-brain axis in metabolic diseases. Int. J. Biol. Sci. 18, 1706–1723 (2022).
Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Jung, S. M., Sanchez-Gurmaches, J. & Guertin, D. A. Brown adipose tissue development and metabolism. Handb. Exp. Pharmacol. 251, 3–36 (2019).
Yang, F. T. & Stanford, K. I. Batokines: mediators of inter-tissue communication (a mini-review). Curr. Obes. Rep. 11, 1–9 (2022).
Scheele, C. & Wolfrum, C. Brown adipose crosstalk in tissue plasticity and human metabolism. Endocr. Rev. 41, 53–65 (2020).
Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 22, 1397–1409 (2008).
Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
Timmons, J. A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl Acad. Sci. USA 104, 4401–4406 (2007).
Sanchez-Gurmaches, J. & Guertin, D. A. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat. Commun. 5, 4099 (2014).
Schulz, T. J. et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc. Natl Acad. Sci. USA 108, 143–148 (2011).
Yang Loureiro, Z. et al. Wnt signaling preserves progenitor cell multipotency during adipose tissue development. Nat. Metab. 5, 1014–1028 (2023).
Palani, N. P. et al. Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots. Nat. Metab. 5, 996–1013 (2023).
Demine, S., Renard, P. & Arnould, T. Mitochondrial uncoupling: a key controller of biological processes in physiology and diseases. Cells 8, 795 (2019).
Kalinovich, A. V., de Jong, J. M., Cannon, B. & Nedergaard, J. UCP1 in adipose tissues: two steps to full browning. Biochimie 134, 127–137 (2017).
Lam, Y. Y. & Ravussin, E. Analysis of energy metabolism in humans: a review of methodologies. Mol. Metab. 5, 1057–1071 (2016).
Cani, P. D. et al. Microbial regulation of organismal energy homeostasis. Nat. Metab. 1, 34–46 (2019).
Buchholz, A. C. & Schoeller, D. A. Is a calorie a calorie? Am. J. Clin. Nutr. 79, 899S–906S (2004).
Cani, P. D. & Van Hul, M. Mediterranean diet, gut microbiota and health: when age and calories do not add up! Gut 69, 1167–1168 (2020).
Westerterp, K. R. Perception, passive overfeeding and energy metabolism. Physiol. Behav. 89, 62–65 (2006).
Swaminathan, R. et al. Thermic effect of feeding carbohydrate, fat, protein and mixed meal in lean and obese subjects. Am. J. Clin. Nutr. 42, 177–181 (1985).
Calcagno, M. et al. The thermic effect of food: a review. J. Am. Coll. Nutr. 38, 547–551 (2019).
Du, S., Rajjo, T., Santosa, S. & Jensen, M. D. The thermic effect of food is reduced in older adults. Horm. Metab. Res. 46, 365–369 (2014).
Binns, A., Gray, M. & Di Brezzo, R. Thermic effect of food, exercise, and total energy expenditure in active females. J. Sci. Med. Sport 18, 204–208 (2015).
Halton, T. L. & Hu, F. B. The effects of high protein diets on thermogenesis, satiety and weight loss: a critical review. J. Am. Coll. Nutr. 23, 373–385 (2004).
Macdonald, I. A. A review of recent evidence relating to sugars, insulin resistance and diabetes. Eur. J. Nutr. 55, 17–23 (2016).
Fuglsang-Nielsen, R. et al. Effects of whey protein and dietary fiber intake on insulin sensitivity, body composition, energy expenditure, blood pressure, and appetite in subjects with abdominal obesity. Eur. J. Clin. Nutr. 75, 611–619 (2021).
Meslier, V. et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut 69, 1258–1268 (2020).
Reynolds, A. N., Akerman, A. P. & Mann, J. Dietary fibre and whole grains in diabetes management: systematic review and meta-analyses. PLoS Med. 17, e1003053 (2020).
Thyfault, J. P. & Bergouignan, A. Exercise and metabolic health: beyond skeletal muscle. Diabetologia 63, 1464–1474 (2020).
Richter, E. A. & Ruderman, N. B. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem. J. 418, 261–275 (2009).
Liang, H. & Ward, W. F. PGC-1α: a key regulator of energy metabolism. Adv. Physiol. Educ. 30, 145–151 (2006).
Stanford, K. I. et al. 12,13-DiHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e3 (2018).
Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 23, 631–637 (2017).
Reutrakul, S. & Van Cauter, E. Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes. Metabolism 84, 56–66 (2018).
Spiegel, K., Knutson, K., Leproult, R., Tasali, E. & Van Cauter, E. Sleep loss: a novel risk factor for insulin resistance and type 2 diabetes. J. Appl. Physiol. 99, 2008–2019 (2005).
Zhu, B., Shi, C., Park, C. G., Zhao, X. & Reutrakul, S. Effects of sleep restriction on metabolism-related parameters in healthy adults: a comprehensive review and meta-analysis of randomized controlled trials. Sleep Med. Rev. 45, 18–30 (2019).
Soltanieh, S., Solgi, S., Ansari, M., Santos, H. O. & Abbasi, B. Effect of sleep duration on dietary intake, desire to eat, measures of food intake and metabolic hormones: a systematic review of clinical trials. Clin. Nutr. ESPEN 45, 55–65 (2021).
Frank, S. et al. Diet and sleep physiology: public health and clinical implications. Front. Neurol. 8, 393 (2017).
Cooper, C. B., Neufeld, E. V., Dolezal, B. A. & Martin, J. L. Sleep deprivation and obesity in adults: a brief narrative review. BMJ Open Sport Exerc. Med. 4, e000392 (2018).
Shan, Z. et al. Sleep duration and risk of type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 38, 529–537 (2015).
Ayas, N. T. et al. A prospective study of self-reported sleep duration and incident diabetes in women. Diabetes Care 26, 380–384 (2003).
Smith, S. M. & Vale, W. W. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin. Neurosci. 8, 383–395 (2006).
Hirotsu, C., Tufik, S. & Andersen, M. L. Interactions between sleep, stress, and metabolism: from physiological to pathological conditions. Sleep Sci. 8, 143–152 (2015).
Sato, F., Kohsaka, A., Bhawal, U. K. & Muragaki, Y. Potential roles of Dec and Bmal1 genes in interconnecting circadian clock and energy metabolism. Int. J. Mol. Sci. 19, 781 (2018).
Nowak, N., Rawleigh, A. & Brown, S. A. Circadian clocks, sleep, and metabolism. Adv. Exp. Med. Biol. 1344, 21–42 (2021).
Broussard, J. L., Ehrmann, D. A., Van Cauter, E., Tasali, E. & Brady, M. J. Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann. Intern. Med. 157, 549–557 (2012).
Sweeney, E. L., Jeromson, S., Hamilton, D. L., Brooks, N. E. & Walshe, I. H. Skeletal muscle insulin signaling and whole-body glucose metabolism following acute sleep restriction in healthy males. Physiol. Rep. 5, e13498 (2017).
Schmid, S. M., Hallschmid, M., Jauch-Chara, K., Born, J. & Schultes, B. A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J. Sleep Res. 17, 331–334 (2008).
Liu, S., Wang, X., Zheng, Q., Gao, L. & Sun, Q. Sleep deprivation and central appetite regulation. Nutrients 14, 5196 (2022).
van Egmond, L. T. et al. Effects of acute sleep loss on leptin, ghrelin, and adiponectin in adults with healthy weight and obesity: a laboratory study. Obesity 31, 635–641 (2023).
Colangeli, L. et al. The crosstalk between gut microbiota and white adipose tissue mitochondria in obesity. Nutrients 15, 1723 (2023).
Backhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).
Rabot, S. et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, 4948–4959 (2010).
Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Muccioli, G. et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 6, 392 (2010).
Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
Chevalier, C. et al. Gut microbiota orchestrates energy homeostasis during cold. Cell 163, 1360–1374 (2015).
Geurts, L. et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nat. Commun. 6, 6495 (2015).
Suarez-Zamorano, N. et al. Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat. Med. 21, 1497–1501 (2015).
Gibson, G. R. et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 14, 491–502 (2017).
Hill, C. et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).
Salminen, S. et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat. Rev. Gastroenterol. Hepatol. 18, 649–667 (2021).
Aguilar-Toala, J. E. et al. Postbiotics — when simplification fails to clarify. Nat. Rev. Gastroenterol. Hepatol. 18, 825–826 (2021).
Vinderola, G., Sanders, M. E. & Salminen, S. The concept of postbiotics. Foods 11, 1077 (2022).
Rinott, E. et al. Effects of diet-modulated autologous fecal microbiota transplantation on weight regain. Gastroenterology 160, 158–173.e10 (2021).
Wolters, M. et al. Dietary fat, the gut microbiota, and metabolic health — a systematic review conducted within the MyNewGut project. Clin. Nutr. 38, 2504–2520 (2019).
Mocanu, V. et al. Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial. Nat. Med. 27, 1272–1279 (2021).
Rastall, R. A. et al. Structure and function of non-digestible carbohydrates in the gut microbiome. Benef. Microbes 13, 95–168 (2022).
Bartlett, A. & Kleiner, M. Dietary protein and the intestinal microbiota: an understudied relationship. iScience 25, 105313 (2022).
Suriano, F. et al. Fat and not sugar as the determining factor for gut microbiota changes, obesity, and related metabolic disorders in mice. Am. J. Physiol. Endocrinol. Metab. 324, E85–E96 (2023).
Allen, J. M. et al. Exercise alters gut microbiota composition and function in lean and obese humans. Med. Sci. Sports Exerc. 50, 747–757 (2018).
Sun, J., Fang, D., Wang, Z. & Liu, Y. Sleep deprivation and gut microbiota dysbiosis: current understandings and implications. Int J. Mol. Sci. 24, 9603 (2023).
Yoon, J. C. et al. Peroxisome proliferator-activated receptor γ target gene encoding a novel angiopoietin-related protein associated with adipose differentiation. Mol. Cell Biol. 20, 5343–5349 (2000).
Kersten, S. et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999).
Wang, H. & Eckel, R. H. Lipoprotein lipase: from gene to obesity. Am. J. Physiol. Endocrinol. Metab. 297, E271–288 (2009).
Fleissner, C. K. et al. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br. J. Nutr. 104, 919–929 (2010).
Kubeck, R. et al. Dietary fat and gut microbiota interactions determine diet-induced obesity in mice. Mol. Metab. 5, 1162–1174 (2016).
Moretti, C. H. et al. Germ-free mice are not protected against diet-induced obesity and metabolic dysfunction. Acta Physiol. 231, e13581 (2021).
Jacouton, E. et al. Lactobacillus rhamnosus CNCMI-4317 modulates Fiaf/Angptl4 in intestinal epithelial cells and circulating level in mice. PLoS One 10, e0138880 (2015).
Kim, H. K. et al. Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight. Diabetes 59, 2772–2780 (2010).
Slavin, J. Fiber and prebiotics: mechanisms and health benefits. Nutrients 5, 1417–1435 (2013).
Roberfroid, M. et al. Prebiotic effects: metabolic and health benefits. Br. J. Nutr. 104, S1–S63 (2010).
Nicholson, J. K. et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).
Cronin, P., Joyce, S. A., O’Toole, P. W. & O’Connor, E. M. Dietary fibre modulates the gut microbiota. Nutrients 13, 1655 (2021).
Bergman, E. N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567–590 (1990).
Blaak, E. E. et al. Short chain fatty acids in human gut and metabolic health. Benef. Microbes 11, 411–455 (2020).
Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).
Dalile, B., Van Oudenhove, L., Vervliet, B. & Verbeke, K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat. Rev. Gastroenterol. Hepatol. 16, 461–478 (2019).
Sanna, S. et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat. Genet. 51, 600–605 (2019).
Anachad, O., Taouil, A., Taha, W., Bennis, F. & Chegdani, F. The implication of short-chain fatty acids in obesity and diabetes. Microbiol. Insights 16, 11786361231162720 (2023).
Rastelli, M., Cani, P. D. & Knauf, C. The gut microbiome influences host endocrine functions. Endocr. Rev. 40, 1271–1284 (2019).
Chambers, E. S. et al. Acute oral sodium propionate supplementation raises resting energy expenditure and lipid oxidation in fasted humans. Diabetes Obes. Metab. 20, 1034–1039 (2018).
Chambers, E. S., Preston, T., Frost, G. & Morrison, D. J. Role of gut microbiota-generated short-chain fatty acids in metabolic and cardiovascular health. Curr. Nutr. Rep. 7, 198–206 (2018).
Chambers, E. S. et al. Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial. Gut 68, 1430–1438 (2019).
Byrne, C. S. et al. Effects of inulin propionate ester incorporated into palatable food products on appetite and resting energy expenditure: a randomised crossover study. Nutrients 11, 861 (2019).
Hong, Y. H. et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146, 5092–5099 (2005).
Dewulf, E. et al. Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. J. Nutr. Biochem. 22, 712–722 (2011).
Dewulf, E. M. et al. Evaluation of the relationship between GPR43 and adiposity in human. Nutr. Metab. 10, 11 (2013).
Yu, H., Li, R., Huang, H., Yao, R. & Shen, S. Short-chain fatty acids enhance the lipid accumulation of 3T3-L1 cells by modulating the expression of enzymes of fatty acid metabolism. Lipids 53, 77–84 (2018).
May, K. S. & den Hartigh, L. J. Modulation of adipocyte metabolism by microbial short-chain fatty acids. Nutrients 13, 3666 (2021).
Hu, J. et al. Short-chain fatty acid acetate stimulates adipogenesis and mitochondrial biogenesis via GPR43 in brown adipocytes. Endocrinology 157, 1881–1894 (2016).
Li, Z. et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut 67, 1269–1279 (2018).
Sharma, M., Li, Y., Stoll, M. L. & Tollefsbol, T. O. The epigenetic connection between the gut microbiome in obesity and diabetes. Front. Genet. 10, 1329 (2019).
Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Cani, P. D. Human gut microbiome: hopes, threats and promises. Gut 67, 1716–1725 (2018).
Regnier, M., Van Hul, M., Knauf, C. & Cani, P. D. Gut microbiome, endocrine control of gut barrier function and metabolic diseases. J. Endocrinol. 248, R67–R82 (2021).
Leclercq, S. et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc. Natl Acad. Sci. USA 111, E4485–E4493 (2014).
Brun, P. et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G518–G525 (2007).
Cani, P. D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091–1103 (2009).
Suriano, F. et al. Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: two sides of the same coin. Microbiome 9, 147 (2021).
Thaiss, C. A. et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 359, 1376–1383 (2018).
Chassaing, B. et al. Lack of soluble fiber drives diet-induced adiposity in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G528-41 (2015).
Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066–9071 (2013).
Everard, A. et al. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J. 8, 2116–2130 (2014).
Guo, X. et al. High fat diet alters gut microbiota and the expression of paneth cell-antimicrobial peptides preceding changes of circulating inflammatory cytokines. Mediators Inflamm. 2017, 9474896 (2017).
Paone, P. & Cani, P. D. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 69, 2232–2243 (2020).
Caesar, R. et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 61, 1701–1707 (2012).
Hersoug, L. G., Moller, P. & Loft, S. Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obes. Rev. 17, 297–312 (2016).
Chung, S. et al. Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology 147, 5340–5351 (2006).
Poulain-Godefroy, O. & Froguel, P. Preadipocyte response and impairment of differentiation in an inflammatory environment. Biochem. Biophys. Res. Commun. 356, 662–667 (2007).
Poulain-Godefroy, O., Lecoeur, C., Pattou, F., Fruhbeck, G. & Froguel, P. Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1–R7 (2008).
Cawthorn, W. P., Heyd, F., Hegyi, K. & Sethi, J. K. Tumour necrosis factor-α inhibits adipogenesis via a β-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Differ. 14, 1361–1373 (2007).
Luo, X. et al. β-Catenin protein utilized by tumour necrosis factor-alpha in porcine preadipocytes to suppress differentiation. BMB Rep. 42, 338–343 (2009).
Geurts, L. et al. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue. Front. Microbiol. 2, 149 (2011).
Than, A. et al. Apelin inhibits adipogenesis and lipolysis through distinct molecular pathways. Mol. Cell Endocrinol. 362, 227–241 (2012).
Zhao, M. & Chen, X. Effect of lipopolysaccharides on adipogenic potential and premature senescence of adipocyte progenitors. Am. J. Physiol. Endocrinol. Metab. 309, E334–344 (2015).
Chang, C. C. et al. Lipopolysaccharide promoted proliferation and adipogenesis of preadipocytes through JAK/STAT and AMPK-regulated cPLA2 expression. Int. J. Med. Sci. 16, 167–179 (2019).
Luche, E. et al. Metabolic endotoxemia directly increases the proliferation of adipocyte precursors at the onset of metabolic diseases through a CD14-dependent mechanism. Mol. Metab. 2, 281–291 (2013).
Ding, S. et al. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One 5, e12191 (2010).
Anhê, F. F., Barra, N. G., Cavallari, J. F., Henriksbo, B. D. & Schertzer, J. D. Metabolic endotoxemia is dictated by the type of lipopolysaccharide. Cell Rep. 36, 109691 (2021).
Moreno-Navarrete, J. M. et al. Lysozyme is a component of the innate immune system linked to obesity associated-chronic low-grade inflammation and altered glucose tolerance. Clin. Nutr. 40, 1420–1429 (2021).
Chi, W. et al. Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1. PLoS One 9, e97675 (2014).
Foley, K. P. et al. Inflammation promotes adipocyte lipolysis via IRE1 kinase. J. Biol. Chem. 296, 100440 (2021).
Schertzer, J. D. et al. NOD1 activators link innate immunity to insulin resistance. Diabetes 60, 2206–2215 (2011).
Gao, H. et al. Accumulation of microbial DNAs promotes to islet inflammation and beta cell abnormalities in obesity in mice. Nat. Commun. 13, 565 (2022).
Jialal, I., Kaur, H. & Devaraj, S. Toll-like receptor status in obesity and metabolic syndrome: a translational perspective. J. Clin. Endocrinol. Metab. 99, 39–48 (2014).
Guerrero-Romero, F. et al. Association between the expression of TLR4, TLR2, and MyD88 with low-grade chronic inflammation in individuals with metabolically healthy obesity. Mol. Biol. Rep. 50, 4723–4728 (2023).
Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).
Guadagnini, D. et al. Microbiota determines insulin sensitivity in TLR2-KO mice. Life Sci. 234, 116793 (2019).
Denou, E. et al. Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Mol. Med. 7, 259–274 (2015).
Rojas, I. Y. et al. Kynurenine-induced aryl hydrocarbon receptor signaling in mice causes body mass gain, liver steatosis, and hyperglycemia. Obesity 29, 337–349 (2021).
Favennec, M. et al. The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity 23, 2066–2074 (2015).
Vujkovic-Cvijin, I. et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci. Transl. Med. 5, 193ra91 (2013).
Alexander, D. L., Ganem, L. G., Fernandez-Salguero, P., Gonzalez, F. & Jefcoate, C. R. Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis. J. Cell Sci. 111, 3311–3322 (1998).
Dou, H. et al. Aryl hydrocarbon receptor (AhR) regulates adipocyte differentiation by assembling CRL4B ubiquitin ligase to target PPARγ for proteasomal degradation. J. Biol. Chem. 294, 18504–18515 (2019).
Agudelo, L. Z. et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. Cell Metab. 27, 378–392.e5 (2018).
Laurans, L. et al. Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat. Med. 24, 1113–1120 (2018).
Huang, T. et al. Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling. Nat. Commun. 13, 3489 (2022).
Virtue, A. T. et al. The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs. Sci. Transl. Med. 11, eaav1892 (2019).
Park, J. et al. Bioactive lipids and their derivatives in biomedical applications. Biomol. Ther. 29, 465–482 (2021).
Ayub, M., Jin, H. K. & Bae, J. S. Novelty of sphingolipids in the central nervous system physiology and disease: focusing on the sphingolipid hypothesis of neuroinflammation and neurodegeneration. Int. J. Mol. Sci. 22, 7353 (2021).
Leuti, A. et al. Bioactive lipids, inflammation and chronic diseases. Adv. Drug Deliv. Rev. 159, 133–169 (2020).
Cani, P. D. et al. Endocannabinoids — at the crossroads between the gut microbiota and host metabolism. Nat. Rev. Endocrinol. 12, 133–143 (2016).
Russo, R. et al. Gut-brain axis: role of lipids in the regulation of inflammation, pain and CNS diseases. Curr. Med. Chem. 25, 3930–3952 (2018).
Lavelle, A. & Sokol, H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 223–237 (2020).
Collins, S. L., Stine, J. G., Bisanz, J. E., Okafor, C. D. & Patterson, A. D. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat. Rev. Microbiol. 21, 236–247 (2023).
Lefort, C. & Cani, P. D. The liver under the spotlight: bile acids and oxysterols as pivotal actors controlling metabolism. Cells 10, 400 (2021).
Dawson, P. A. & Karpen, S. J. Intestinal transport and metabolism of bile acids. J. Lipid Res. 56, 1085–1099 (2015).
Ahmad, T. R. & Haeusler, R. A. Bile acids in glucose metabolism and insulin signalling — mechanisms and research needs. Nat. Rev. Endocrinol. 15, 701–712 (2019).
Chen, X., Lou, G., Meng, Z. & Huang, W. TGR5: a novel target for weight maintenance and glucose metabolism. Exp. Diabetes Res. 2011, 853501 (2011).
Velazquez-Villegas, L. A. et al. TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat. Commun. 9, 245 (2018).
Broeders, E. P. et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 22, 418–426 (2015).
Pellicciari, R. et al. Discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J. Med. Chem. 52, 7958–7961 (2009).
Murakami, M. et al. Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects. Springerplus 2, 20 (2013).
Bala, V. et al. Release of GLP-1 and PYY in response to the activation of G protein-coupled bile acid receptor TGR5 is mediated by Epac/PLC-epsilon pathway and modulated by endogenous H2S. Front. Physiol. 5, 420 (2014).
Devane, W. A., Dysarz, F. A. III, Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).
Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).
D’Eon, T. M. et al. The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes 57, 1262–1268 (2008).
Starowicz, K. M. et al. Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet. Obesity 16, 553–565 (2008).
Sarzani, R. et al. Altered pattern of cannabinoid type 1 receptor expression in adipose tissue of dysmetabolic and overweight patients. Metabolism 58, 361–367 (2009).
Gasperi, V. et al. Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol. Life Sci. 64, 219–229 (2007).
Everard, A. et al. Intestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis. Nat. Commun. 10, 457 (2019).
Geurts, L., Muccioli, G. G., Delzenne, N. M. & Cani, P. D. Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia. PLoS One 8, e55963 (2013).
Suriano, F. et al. Exploring the endocannabinoidome in genetically obese (ob/ob) and diabetic (db/db) mice: links with inflammation and gut microbiota. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1867, 159056 (2022).
Manca, C. et al. Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling. J. Lipid Res. 61, 70–85 (2020).
Suriano, F. et al. A lipidomics- and transcriptomics-based analysis of the intestine of genetically obese (ob/ob) and diabetic (db/db) mice: links with inflammation and gut microbiota. Cells 12, 411 (2023).
Cohen, L. J. et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 549, 48–53 (2017).
Misheva, M., Johnson, J. & McCullagh, J. Role of oxylipins in the inflammatory-related diseases NAFLD, obesity, and type 2 diabetes. Metabolites 12, 1238 (2022).
Avila-Roman, J. et al. Impact of gut microbiota on plasma oxylipins profile under healthy and obesogenic conditions. Clin. Nutr. 40, 1475–1486 (2021).
Gurup, A. et al. Effect of acute exercise on 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) levels in obese male adolescents. Clin. Endocrinol. 99, 174–181 (2023).
Moens de Hase, E. et al. Dysosmobacter welbionis effects on glucose, lipid and energy metabolism are associated with specific bioactive lipids. J. Lipid Res. 64, 100437 (2023).
Le Roy, T. et al. Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice. Gut 71, 534–543 (2022).
Fernandez-Veledo, S. & Vendrell, J. Gut microbiota-derived succinate: friend or foe in human metabolic diseases? Rev. Endocr. Metab. Disord. 20, 439–447 (2019).
Ariza, A. C., Deen, P. M. & Robben, J. H. The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions. Front. Endocrinol. 3, 22 (2012).
Louis, P. & Flint, H. J. Formation of propionate and butyrate by the human colonic microbiota. Environ. Microbiol. 19, 29–41 (2017).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).
Chia, L. W. et al. Deciphering the trophic interaction between Akkermansia muciniphila and the butyrogenic gut commensal Anaerostipes caccae using a metatranscriptomic approach. Antonie Van Leeuwenhoek 111, 859–873 (2018).
Cani, P. D., Depommier, C., Derrien, M., Everard, A. & de Vos, W. M. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat. Rev. Gastroenterol. Hepatol. 19, 625–637 (2022).
Wang, K. et al. Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids. Cell Rep. 26, 222–235.e5 (2019).
Sadagopan, N. et al. Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am. J. Hypertens. 20, 1209–1215 (2007).
McCreath, K. J. et al. Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity. Diabetes 64, 1154–1167 (2015).
Monfort-Ferre, D. et al. The gut microbiota metabolite succinate promotes adipose tissue browning in crohn’s disease. J. Crohns Colitis 16, 1571–1583 (2022).
Massier, L. et al. Adipose tissue derived bacteria are associated with inflammation in obesity and type 2 diabetes. Gut 69, 1796–1806 (2020).
Anhê, F. F. et al. Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity. Nat. Metab. 2, 233–242 (2020).
Amar, J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54, 3055–3061 (2011).
de Goffau, M. C. et al. Recognizing the reagent microbiome. Nat. Microbiol. 3, 851–853 (2018).
Church, D. L. et al. Performance and application of 16S rRNA gene cycle sequencing for routine identification of bacteria in the clinical microbiology laboratory. Clin. Microbiol. Rev. 33, e00053-19 (2020).
Sun, J. et al. The visceral adipose tissue bacterial microbiota provides a signature of obesity based on inferred metagenomic functions. Int. J. Obes. 47, 1008–1022 (2023).
Cinti, S. Pink adipocytes. Trends Endocrinol. Metab. 29, 651–666 (2018).
Selma-Royo, M., Calvo Lerma, J., Cortes-Macias, E. & Collado, M. C. Human milk microbiome: from actual knowledge to future perspective. Semin. Perinatol. 45, 151450 (2021).
Collado, M. C., Laitinen, K., Salminen, S. & Isolauri, E. Maternal weight and excessive weight gain during pregnancy modify the immunomodulatory potential of breast milk. Pediatr. Res. 72, 77–85 (2012).
Fernandez, L. & Rodriguez, J. M. Human milk microbiota: origin and potential uses. Nestle Nutr. Inst. Workshop Ser. 94, 75–85 (2020).
Fernandez, L., Pannaraj, P. S., Rautava, S. & Rodriguez, J. M. The microbiota of the human mammary ecosystem. Front. Cell. Infect. Microbiol. 10, 586667 (2020).
Mohandas, S. & Pannaraj, P. S. Beyond the bacterial microbiome: virome of human milk and effects on the developing infant. Nestle Nutr. Inst. Workshop Ser. 94, 86–93 (2020).
Cani, P. D. & Van Hul, M. Microbial signatures in metabolic tissues: a novel paradigm for obesity and diabetes? Nat. Metab. 2, 211–212 (2020).
Bluher, S., Shah, S. & Mantzoros, C. S. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J. Investig. Med. 57, 784–788 (2009).
Suleiman, J. B., Mohamed, M. & Bakar, A. B. A. A systematic review on different models of inducing obesity in animals: advantages and limitations. J. Adv. Vet. Anim. Res. 7, 103–114 (2020).
Healey, G. R., Murphy, R., Brough, L., Butts, C. A. & Coad, J. Interindividual variability in gut microbiota and host response to dietary interventions. Nutr. Rev. 75, 1059–1080 (2017).
Schlomann, B. H. & Parthasarathy, R. Timescales of gut microbiome dynamics. Curr. Opin. Microbiol. 50, 56–63 (2019).
Cerdó, T., García-Santos, J. A., Bermúdez, M. G. & Campoy, C. The role of probiotics and prebiotics in the prevention and treatment of obesity. Nutrients 11, 635 (2019).
Nearing, J. T., Comeau, A. M. & Langille, M. G. I. Identifying biases and their potential solutions in human microbiome studies. Microbiome 9, 113 (2021).
Bharti, R. & Grimm, D. G. Current challenges and best-practice protocols for microbiome analysis. Brief. Bioinform 22, 178–193 (2021).
Levitan, O. et al. The gut microbiome — does stool represent right? Heliyon 9, e13602 (2023).
Chikina, A. & Matic Vignjevic, D. At the right time in the right place: how do luminal gradients position the microbiota along the gut? Cell Dev. 168, 203712 (2021).
Zoetendal, E. G. et al. Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl. Env. Microbiol. 68, 3401–3407 (2002).
Vaga, S. et al. Compositional and functional differences of the mucosal microbiota along the intestine of healthy individuals. Sci. Rep. 10, 14977 (2020).
Canfora, E. E., Meex, R. C. R., Venema, K. & Blaak, E. E. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 15, 261–273 (2019).
Ranjan, R., Rani, A., Metwally, A., McGee, H. S. & Perkins, D. L. Analysis of the microbiome: advantages of whole genome shotgun versus 16S amplicon sequencing. Biochem. Biophys. Res. Commun. 469, 967–977 (2016).
Sharpton, T. J. An introduction to the analysis of shotgun metagenomic data. Front. Plant. Sci. 5, 209 (2014).
Van Hul, M. et al. From correlation to causality: the case of Subdoligranulum. Gut Microbes 12, 1–13 (2020).
Chusyd, D. E., Wang, D., Huffman, D. M. & Nagy, T. R. Relationships between rodent white adipose fat pads and human white adipose fat depots. Front. Nutr. 3, 10 (2016).
Borgeson, E., Boucher, J. & Hagberg, C. E. Of mice and men: pinpointing species differences in adipose tissue biology. Front. Cell Dev. Biol. 10, 1003118 (2022).
Bagchi, D. P. & MacDougald, O. A. Identification and dissection of diverse mouse adipose depots. J. Vis. Exp. https://doi.org/10.3791/59499 (2019).
Vitali, A. et al. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J. Lipid Res. 53, 619–629 (2012).
Cohen, C. A., Shea, A. A., Heffron, C. L., Schmelz, E. M. & Roberts, P. C. Intra-abdominal fat depots represent distinct immunomodulatory microenvironments: a murine model. PLoS One 8, e66477 (2013).
Foster, M. T. et al. Transplantation of non-visceral fat to the visceral cavity improves glucose tolerance in mice: investigation of hepatic lipids and insulin sensitivity. Diabetologia 54, 2890–2899 (2011).
Wueest, S., Yang, X., Liu, J., Schoenle, E. J. & Konrad, D. Inverse regulation of basal lipolysis in perigonadal and mesenteric fat depots in mice. Am. J. Physiol. Endocrinol. Metab. 302, E153–160 (2012).
Stenkula, K. G. & Erlanson-Albertsson, C. Adipose cell size: importance in health and disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R284–R295 (2018).
Kowaltowski, A. J. Cold exposure and the metabolism of mice, men, and other wonderful creatures. Physiology 37, 253–259 (2022).
Armani, A. et al. Nutraceuticals in brown adipose tissue activation. Cells 11, 3996 (2022).
Choi, Y. & Yu, L. Natural bioactive compounds as potential browning agents in white adipose tissue. Pharm. Res. 38, 549–567 (2021).
Reynes, B., Palou, M., Rodriguez, A. M. & Palou, A. Regulation of adaptive thermogenesis and browning by prebiotics and postbiotics. Front. Physiol. 9, 1908 (2018).
Zhou, L., Xiao, X., Zhang, Q., Zheng, J. & Deng, M. Deciphering the anti-obesity benefits of resveratrol: the “gut microbiota-adipose tissue” axis. Front. Endocrinol. 10, 413 (2019).
Hui, S. et al. Resveratrol enhances brown adipose tissue activity and white adipose tissue browning in part by regulating bile acid metabolism via gut microbiota remodeling. Int. J. Obes. 44, 1678–1690 (2020).
Liao, W. et al. Resveratrol-induced white adipose tissue browning in obese mice by remodeling fecal microbiota. Molecules 23, 3356 (2018).
Baskaran, P., Krishnan, V., Ren, J. & Thyagarajan, B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br. J. Pharmacol. 173, 2369–2389 (2016).
Kida, R. et al. Direct action of capsaicin in brown adipogenesis and activation of brown adipocytes. Cell Biochem. Funct. 34, 34–41 (2016).
Lee, S. G., Parks, J. S. & Kang, H. W. Quercetin, a functional compound of onion peel, remodels white adipocytes to brown-like adipocytes. J. Nutr. Biochem. 42, 62–71 (2017).
Pei, Y. et al. Effect of quercetin on nonshivering thermogenesis of brown adipose tissue in high-fat diet-induced obese mice. J. Nutr. Biochem. 88, 108532 (2021).
Sheng, L. et al. Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila. FASEB J. 32, 6371–6384 (2018).
Li, C. et al. Berberine ameliorates obesity by inducing GDF15 secretion by brown adipocytes. Endocrinology 164, bqad035 (2023).
Xu, Y. et al. Berberine modulates deacetylation of PPARγ to promote adipose tissue remodeling and thermogenesis via AMPK/SIRT1 pathway. Int. J. Biol. Sci. 17, 3173–3187 (2021).
Wu, L. et al. Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans. Cell Death Dis. 10, 468 (2019).
Regnier, M. et al. Rhubarb supplementation prevents diet-induced obesity and diabetes in association with increased Akkermansia muciniphila in mice. Nutrients 12, 2932 (2020).
Regnier, M. et al. Inulin increases the beneficial effects of rhubarb supplementation on high-fat high-sugar diet-induced metabolic disorders in mice: impact on energy expenditure, brown adipose tissue activity, and microbiota. Gut Microbes 15, 2178796 (2023).
Anhe, F. F. et al. Treatment with camu camu (Myrciaria dubia) prevents obesity by altering the gut microbiota and increasing energy expenditure in diet-induced obese mice. Gut 68, 453–464 (2019).
Zheng, X. et al. Membrane protein Amuc_1100 derived from Akkermansia muciniphila facilitates lipolysis and browning via activating the AC3/PKA/HSL pathway. Microbiol. Spectr. 11, e0432322 (2023).
Deng, L. et al. Diverse effects of different Akkermansia muciniphila genotypes on Brown adipose tissue inflammation and whitening in a high-fat-diet murine model. Microb. Pathog. 147, 104353 (2020).
Depommier, C. et al. Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice. Gut Microbes 11, 1231–1245 (2020).
Dao, M. C. et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65, 426–436 (2016).
Agus, A., Clement, K. & Sokol, H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut 70, 1174–1182 (2020).
Scheja, L. & Heeren, J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat. Rev. Endocrinol. 15, 507–524 (2019).
James, D. E., Stockli, J. & Birnbaum, M. J. The aetiology and molecular landscape of insulin resistance. Nat. Rev. Mol. Cell Biol. 22, 751–771 (2021).
Morigny, P., Boucher, J., Arner, P. & Langin, D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat. Rev. Endocrinol. 17, 276–295 (2021).
Clemente-Suarez, V. J. et al. The role of adipokines in health and disease. Biomedicines 11, 1290 (2023).
Lazar, V. et al. Gut microbiota, host organism, and diet trialogue in diabetes and obesity. Front. Nutr. 6, 21 (2019).
Jardon, K. M., Canfora, E. E., Goossens, G. H. & Blaak, E. E. Dietary macronutrients and the gut microbiome: a precision nutrition approach to improve cardiometabolic health. Gut 71, 1214–1226 (2022).
Gerard, C. & Vidal, H. Impact of gut microbiota on host glycemic control. Front. Endocrinol. 10, 29 (2019).
Acknowledgements
P.D.C. is Honorary Research Director at FRS-FNRS (Fonds de la Recherche Scientifique) and a recipient of grants from FNRS (Projet de Recherche PDR-convention: FNRS T.0030.21, CDR-convention: J.0027.22, FRFS-WELBIO: WELBIO-CR-2022A-02, EOS: programme no. 40007505) and ARC (action de recherche concertée: ARC19/24-096) and La Caixa (NeuroGut).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
P.D.C. is an inventor on patent applications dealing with the use of specific bacteria and components in the treatment of different diseases. P.D.C. was co-founder of The Akkermansia Company SA and Enterosys. M.V.H. declares no competing interests.
Peer review
Peer review information
Nature Reviews Gastroenterology & Hepatology thanks Philip Calder, Remy Burcelin, and the other, anonymous, reviewer for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
World Obesity Federation: https://www.worldobesityday.org/resources/entry/world-obesity-atlas-2023
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cani, P.D., Van Hul, M. Gut microbiota in overweight and obesity: crosstalk with adipose tissue. Nat Rev Gastroenterol Hepatol 21, 164–183 (2024). https://doi.org/10.1038/s41575-023-00867-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-023-00867-z
This article is cited by
-
Exosomes in the pathogenesis and treatment of cancer-related cachexia
Journal of Translational Medicine (2024)