Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass

Abstract

Diet interventions such as calorie restriction or time-restricted feeding offer potential for weight management, but long-term success is often hindered by poor adherence due to the rewarding effects of sugars. In this study, we demonstrate that sulfur amino acid restriction (SAAR) diets promote rapid fat loss without impairing appetite and physiological locomotion, outperforming diets with restricted branched-chain amino acids. Weekly cycling of SAAR diets preserves metabolic benefits, such as reduced fat mass and improved glucose sensitivity. Metabolic analysis and in vivo isotope tracing revealed a shift toward carbohydrate oxidation in white and brown adipose tissue (WAT and BAT), and liver during the SAAR diet refeeding state, leading to decreased de novo lipogenesis. Enhanced lipolysis and fatty acid oxidation were observed in the heart, brain, BAT, lungs, etc. The reintroduction of methionine or cystine negated these metabolic benefits. Further ¹³C and ²H tracing experiments indicated that cystine, rather than its derivatives like taurine or H₂S, directly regulates adiposity. In a high-fat diet model, SAAR diet led to sustained fat mass reduction, regardless of the timing of intervention. Additionally, cystine levels correlated positively with body mass index (BMI) and total triglycerides in diabetic patients. Our findings highlight SAAR diet as a promising strategy for long-term weight control by modulating systemic glucose and lipid metabolism homeostasis.

Keywords

diet intervention / sulfur amino acid / fat loss / isotope tracing / metabolic flux / glucose and lipid metabolism

References

[1] Blüher M . Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 2019; 15: 288- 98.

[2] Klein S , Gastaldelli A , Yki-Järvinen H et al. Why does obesity cause diabetes? Cell Metab 2022; 34: 11- 20.

[3] Calle EE , Rodriguez C , Walker-Thurmond K et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625- 38.

[4] Lingvay I , Cohen RV , Roux CW et al. Obesity in adults. Lancet 2024; 404: 972- 87.

[5] Demaris KM , White JR . Dapagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes. Drugs Today (Barc) 2013; 49: 289- 301.

[6] Han S , Hagan DL , Taylor JR et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 2008; 57: 1723- 9.

[7] Nguyen NT , Varela JE . Bariatric surgery for obesity and metabolic disorders: state of the art. Nat Rev Gastroenterol Hepatol 2017; 14: 160- 9.

[8] Holst JJ . GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 2024; 6: 1866- 85.

[9] Wilding JPH , Batterham RL , Davies M et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022; 24: 1553- 64.

[10] Yu D , Tomasiewicz JL , Yang SE et al. Calorie-restriction-induced insulin sensitivity is mediated by adipose mTORC2 and not required for lifespan extension. Cell Rep 2019; 29: 236- 48.e3.

[11] Bai M , Wang Y , Han R et al. Intermittent caloric restriction with a modified fasting-mimicking diet ameliorates autoimmunity and promotes recovery in a mouse model of multiple sclerosis. J Nutr Biochem 2021; 87: 108493.

[12] Mitchell SJ , Bernier M , Mattison JA et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab 2019; 29: 221- 8.e3.

[13] Zafar MI , Mills KE , Zheng J et al. Low-glycemic index diets as an intervention for diabetes: a systematic review and meta-analysis. Am J Clin Nutr 2019; 110: 891- 902.

[14] Appleton KM , Tuorila H , Bertenshaw EJ et al. Sweet taste exposure and the subsequent acceptance and preference for sweet taste in the diet: systematic review of the published literature. Am J Clin Nutr 2018; 107: 405- 19.

[15] Suez J , Korem T , Zeevi D et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014; 514: 181- 6.

[16] Fontana L , Cummings NE , Arriola Apelo SI et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep 2016; 16: 520- 30.

[17] Cummings NE , Williams EM , Kasza I et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol 2018; 596: 623- 45.

[18] Neinast M , Murashige D , Arany Z . Branched chain amino acids. Annu Rev Physiol 2019; 81: 139- 64.

[19] Du Y , Meng Q , Zhang Q et al. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids 2012; 43: 725- 34.

[20] Yu D , Richardson NE , Green CL et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab 2021; 33: 905- 22.e6.

[21] Blair MC , Neinast MD , Jang C et al. Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance. Nat Metab 2023; 5: 589- 606.

[22] Bárcena C , Quirós PM , Durand S et al. Methionine restriction extends lifespan in progeroid mice and alters lipid and bile acid metabolism. Cell Rep 2018; 24: 2392- 403.

[23] Li Z , Wang F , Liang B et al. Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication. Signal Transduct Target Ther 2020; 5: 280.

[24] Yu D , Yang S , Miller BR et al. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J 2018; 32: 3471- 82.

[25] Song T , Qin W , Lai Z et al. Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse. Cell Res 2023; 33: 434- 47.

[26] Nichenametla SN , Mattocks DAL , Cooke D et al. Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism. Aging Cell 2022; 21: e13739.

[27] Elshorbagy AK , Smith AD , Kozich V et al. Cysteine and obesity. Obesity (Silver Spring) 2012; 20: 473- 81.

[28] Zhang Z , TeSlaa T , Xu X et al. Serine catabolism generates liver NADPH and supports hepatic lipogenesis. Nat Metab 2021; 3: 1608- 20.

[29] Zhang Z , TeSlaa T , Rabinowitz JD . Reply to: revisiting the role of serine metabolism in hepatic lipogenesis. Nat Metab 2023; 5: 762- 4.

[30] Green CR , Wallace M , Divakaruni AS et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat Chem Biol 2016; 12: 15- 21.

[31] Hui S , Cowan AJ , Zeng X et al. Quantitative fluxomics of circulating metabolites. Cell Metab 2020; 32: 676- 88.e4.

[32] Green CL , Pak HH , Richardson NE et al. Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction. Cell Metab 2022; 34: 209- 26.e5.

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

[34] Song P , Zechner C , Hernandez G et al. The hormone FGF21 stimulates water drinking in response to ketogenic diet and alcohol. Cell Metab 2018; 27: 1338- 47.e4.

[35] Bates MW . Kinetics of ketone body metabolism in fasted and diabetic rats. Am J Physiol 1971; 221: 984- 91.

[36] Srinivasan B , Baratashvili M , van der Zwaag M et al. Extracellular 4'-phosphopantetheine is a source for intracellular coenzyme A synthesis. Nat Chem Biol 2015; 11: 784- 92.

[37] Longchamp A , Mirabella T , Arduini A et al. Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H₂S production. Cell 2018; 173: 117- 29.e14.

[38] Kissová IB , Camougrand N . Glutathione participates in the regulation of mitophagy in yeast. Autophagy 2009; 5: 872- 3.

[39] Costa PRF , Kinra S , D'Almeida V et al. Serum homocysteine and cysteine levels and anthropometric changes: a longitudinal study among Brazilian children and adolescents. J Am Coll Nutr 2018; 37: 80- 6.

[40] Elshorbagy AK , Refsum H , Smith AD et al. The association of plasma cysteine and gamma-glutamyltransferase with BMI and obesity. Obesity (Silver Spring) 2009; 17: 1435- 40.

[41] Elshorbagy AK , Nurk E , Gjesdal CG et al. Homocysteine, cysteine, and body composition in the Hordaland Homocysteine Study: does cysteine link amino acid and lipid metabolism? Am J Clin Nutr 2008; 88: 738- 46.

[42] Lee AH , Orliaguet L , Youm YH et al. Cysteine depletion triggers adipose tissue thermogenesis and weight-loss. bioRxiv[Preprint] 2024: 2024.08.06.606880

[43] Richie JP Jr , Sinha R , Dong Z et al. Dietary methionine and total sulfur amino acid restriction in healthy adults. J Nutr Health Aging 2023; 27: 111- 23.

[44] Olsen T , Stolt E , Øvrebø B et al. Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial. J Transl Med 2024; 22: 40.

[45] Forney LA , Fang H , Sims LC et al. Dietary methionine restriction signals to the brain through fibroblast growth factor 21 to regulate energy balance and remodeling of adipose tissue. Obesity (Silver Spring) 2020; 28: 1912- 21.

[46] Wanders D , Forney LA , Stone KP et al. FGF21 mediates the thermogenic and insulin-sensitizing effects of dietary methionine restriction but not its effects on hepatic lipid metabolism. Diabetes 2017; 66: 858- 67.

[47] Levine ME , Suarez JA , Brandhorst S et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 2014; 19: 407- 17.

[48] Yuan F , Wu S , Zhou Z et al. Leucine deprivation results in antidepressant effects via GCN2 in AgRP neurons. Life Metab. 2023; 2: load004.

[49] Yuan F , Jiang H , Yin H et al. Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation. Nat Commun 2020; 11: 2847.

[50] Neinast MD , Jang C , Hui S et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab 2019; 29: 417- 29.e4.

[51] Uchiyama J , Akiyama M , Hase K et al. Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species. Cell Rep 2022; 38: 110479.

[52] Zhu J , Berisa M , Schwörer S et al. Transsulfuration activity can support cell growth upon extracellular cysteine limitation. Cell Metab 2019; 30: 865- 76.e5.

[53] Singh P , Gollapalli K , Mangiola S et al. Taurine deficiency as a driver of aging. Science 2023; 380: eabn9257.

[54] Wei W , Lyu X , Markhard AL et al. PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity. Nature 2024; 633: 182- 8.

[55] Granic A , Mendonça N , Sayer AA et al. Low protein intake, muscle strength and physical performance in the very old: the Newcastle 85+ Study. Clin Nutr 2018; 37: 2260- 70.

[56] Castaneda C , Charnley JM , Evans WJ et al. Elderly women accommodate to a low-protein diet with losses of body cell mass, muscle function, and immune response. Am J Clin Nutr 1995; 62: 30- 9.

[57] Gow ML , Jebeile H , House ET et al. Efficacy, safety and accept-ability of a very-low-energy diet in adolescents with obesity: a fast track to health sub-study. Nutrients 2024; 16: 3125.

[58] Janssen TAH , Van Every DW , Phillips SM . The impact and utility of very low-calorie diets: the role of exercise and protein in preserving skeletal muscle mass. Curr Opin Clin Nutr Metab Care 2023; 26: 521- 7.

RIGHTS & PERMISSIONS

The Author(s). Published by Oxford University Press on behalf of Higher Education Press.