Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible.
C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated.
In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity.
This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including ‘browning’ and enhancement of hepatic mitochondrial function.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Eriksson S, Eriksson KF, Bondesson L . Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Med Scand 1986; 220: 83–88.
Parnell JA, Reimer RA . Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr 2009; 89: 1751–1759.
Cani PD, Joly E, Horsmans Y, Delzenne NM . Oligofructose promotes satiety in healthy human: a pilot study. Eur J Clin Nutr 2006; 60: 567–572.
Pasman WJ, Saris WH, Wauters MA, Westerterp-Plantenga MS . Effect of one week of fibre supplementation on hunger and satiety ratings and energy intake. Appetite 1997; 29: 77–87.
So PW, Yu WS, Kuo YT, Wasserfall C, Goldstone AP, Bell JD et al. Impact of resistant starch on body fat patterning and central appetite regulation. PLoS One 2007; 2: e1309.
Keenan MJ, Zhou J, McCutcheon KL, Raggio AM, Bateman HG, Todd E et al. Effects of resistant starch, a non-digestible fermentable fiber, on reducing body fat. Obesity (Silver Spring) 2006; 14: 1523–1534.
Cani P, Neyrinck A, Maton N, Delzenne N . Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obesity Res 2005; 13: 1000–1007.
Anastasovska J, Arora T, Sanchez Canon GJ, Parkinson JR, Touhy K, Gibson GR et al. Fermentable carbohydrate alters hypothalamic neuronal activity and protects against the obesogenic environment. Obesity (Silver Spring) 2012; 20: 1016–1023.
Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT . Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 1987; 28: 1221–1227.
Robertson MD . Metabolic cross talk between the colon and the periphery: implications for insulin sensitivity. Proc Nutr Soc 2007; 66: 351–361.
Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen JL et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 2008; 149: 4519–4526.
Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 2005; 146: 5092–5099.
Kondo T, Kishi M, Fushimi T, Kaga T . Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem 2009; 57: 5982–5986.
Yamashita H, Fujisawa K, Ito E, Idei S, Kawaguchi N, Kimoto M et al. Improvement of obesity and glucose tolerance by acetate in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Biosci Biotechnol Biochem 2007; 71: 1236–1243.
Yamashita H, Maruta H, Jozuka M, Kimura R, Iwabuchi H, Yamato M et al. Effects of acetate on lipid metabolism in muscles and adipose tissues of type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Biosci Biotechnol Biochem 2009; 73: 570–576.
Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 2014; 5: 3611.
Lo S, Tolner B, Taanman JW, Cooper JM, Gu M, Hartley JA et al. Assessment of the significance of mitochondrial DNA damage by chemotherapeutic agents. Int J Oncol 2005; 27: 337–344.
Kamaly N, Kalber T, Thanou M, Bell JD, Miller AD . Folate receptor targeted bimodal liposomes for tumor magnetic resonance imaging. Bioconjug Chem 2009; 20: 648–655.
Kostarelos K, Miller AD . Synthetic, self-assembly ABCD nanoparticles; a structural paradigm for viable synthetic non-viral vectors. Chem Soc Rev 2005; 34: 970–994.
Kalber TL, Kamaly N, So PW, Pugh JA, Bunch J, McLeod CW et al. A low molecular weight folate receptor targeted contrast agent for magnetic resonance tumor imaging. Mol Imaging Biol 2011; 13: 653–662.
Tilg H, Moschen AR . Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol Metab 2008; 19: 371–379.
Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A et al. FAT SIGNALS—lipases and lipolysis in lipid metabolism and signaling. Cell Metab 2012; 15: 279–291.
Wei YZ, Rector RS, Thyfault JP, Ibdah JA . Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroentero 2008; 14: 193–199.
Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19: 302–309.
Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463–468.
Fisher FM, Estall JL, Adams AC, Antonellis PJ, Bina HA, Flier JS et al. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology 2011; 152: 2996–3004.
Emanuelli B, Vienberg SG, Smyth G, Cheng C, Stanford KI, Arumugam M et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest 2014; 124: 515–527.
Harms M, Seale P . Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19: 1252–1263.
Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011; 121: 96–105.
Schon EA, DiMauro S, Hirano M . Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 2012; 13: 878–890.
Varela-Rey M, Embade N, Ariz U, Lu SC, Mato JM, Martinez-Chantar ML . Non-alcoholic steatohepatitis and animal models: understanding the human disease. Int J Biochem Cell Biol 2009; 41: 969–976.
Cummings JH . Short chain fatty acids in the human colon. Gut 1981; 22: 763–779.
Miller AD . Delivery of RNAi therapeutics: work in progress. Expert Rev Med Devices 2013; 10: 781–811.
Kenny GD, Kamaly N, Kalber TL, Brody LP, Sahuri M, Shamsaei E et al. Novel multifunctional nanoparticle mediates siRNA tumour delivery, visualisation and therapeutic tumour reduction in vivo. J Control Release 2011; 149: 111–116.
Canfora EE, Jocken JW, Blaak EE . Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015; 11: 577–591.
Vatner DF, Majumdar SK, Kumashiro N, Petersen MC, Rahimi Y, Gattu AK et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc Natl Acad Sci USA 2015; 112: 1143–1148.
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB . SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol Metab 2008; 19: 65–73.
Prip-Buus C, Perdereau D, Foufelle F, Maury J, Ferre P, Girard J . Induction of fatty-acid-synthase gene expression by glucose in primary culture of rat hepatocytes. Dependency upon glucokinase activity. Eur J Biochem 1995; 230: 309–315.
Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK et al. Acetate dependence of tumors. Cell 2014; 159: 1591–1602.
Hue L, Taegtmeyer H . The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab 2009; 297: E578–E591.
Pessayre D, Fromenty B . NASH: a mitochondrial disease. J Hepatol 2005; 42: 928–940.
Serviddio G, Bellanti F, Tamborra R, Rollo T, Capitanio N, Romano AD et al. Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 2008; 57: 957–965.
Teodoro J, Rolo AP, Oliveira PJ, Palmeira CM . Decreased ANT content in Zucker fatty rats: relevance for altered hepatic mitochondrial bioenergetics in steatosis. FEBS Lett 2006; 580: 2153–2157.
Harris FT, Rahman SM, Hassanein M, Qian J, Hoeksema MD, Chen H et al. Acyl-coenzyme A-binding protein regulates Beta-oxidation required for growth and survival of non-small cell lung cancer. Cancer Prev Res 2014; 7: 748–757.
Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 2014; 156: 304–316.
Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T et al. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab 2014; 19: 593–604.
Sakakibara I, Fujino T, Ishii M, Tanaka T, Shimosawa T, Miura S et al. Fasting-induced hypothermia and reduced energy production in mice lacking acetyl-CoA synthetase 2. Cell Metab 2009; 9: 191–202.
Nedergaard J, Cannon B . The browning of white adipose tissue: some burning issues. Cell Metab 2014; 20: 396–407.
Dolezal BA, Potteiger JA . Concurrent resistance and endurance training influence basal metabolic rate in nondieting individuals. J Appl Physiol 1998; 85: 695–700.
Abdul-Wahed A, Gautier-Stein A, Casteras S, Soty M, Roussel D, Romestaing C et al. A link between hepatic glucose productin and peripheral energy metabolism via hepatokines. Mol Metab 2014; 3: 531–543.
Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol 2009; 15: 5549–5557.
Reisenauer CJ, Bhatt DP, Mitteness DJ, Slanczka ER, Gienger HM, Watt JA et al. Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation. J Neurochem 2011; 117: 264–274.
Wu TC, Chen LK, Tsai SH, Liaw YH, Hwang B . Hepatic steatosis: an experimental model for quantification. Arch Gerontol Geriatr 2011; 52: 164–166.
Sun B, Karin M . Obesity, inflammation, and liver cancer. J Hepatol 2012; 56: 704–713.
Khandekar MJ, Cohen P, Spiegelman BM . Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 2011; 11: 886–895.
We thank Professor Alice Warley and Dr Gema Vizcay-Barrena from the Centre for Ultrastructural Imaging (King's College, London, UK) where TEM was carried out. A549 lung cancer cell lines (Parent and Rho0) were a kind gift from Dr Zhi Yao and Dr Gyorgy Szabadkai. This research was funded by Medical Research Council, UK.
JDB, GF, ELT and MS-A designed the experiments and wrote the manuscript. MS-A performed and analyzed most of the experiments. MS-A, LPB and ADM performed liposome formulation and delivery experiments. HP carried out NMR scans. NN conducted protein expression of A549 cells. All the authors provided critical feedback in preparation and writing the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on International Journal of Obesity website
About this article
Cite this article
Sahuri-Arisoylu, M., Brody, L., Parkinson, J. et al. Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate. Int J Obes 40, 955–963 (2016). https://doi.org/10.1038/ijo.2016.23
Understanding the interplay between food structure, intestinal bacterial fermentation and appetite control
Proceedings of the Nutrition Society (2020)
The Relationship between Circulating Acetate and Human Insulin Resistance before and after Weight Loss in the DiOGenes Study
Molecular and Cellular Endocrinology (2020)
Regulation of thermogenic capacity in brown and white adipocytes by the prebiotic high-esterified pectin and its postbiotic acetate
International Journal of Obesity (2020)