The natural product rotundic acid treats both aging and obesity by inhibiting PTP1B

Abstract

The occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol, and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.

Keywords

aging / obesity / rotundic acid / PTP1B / leptin

References

[1] Kranjac AW, Wagmiller RL. Association between age and obesity over time. Pediatrics 2016;137:e20152096

[2] Pi-Sunyer X. The medical risks of obesity. Postgrad Med 2009;121:21–33

[3] Wang YC, McPherson K, Marsh T, et al. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 2011;378:815–25

[4] Reuser M, Bonneux L, Willekens F. The burden of mortality of obesity at middle and old age is small. A life table analysis of the US Health and Retirement Survey. Eur J Epidemiol 2008;23:601–7

[5] Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity. JAMA 2003;289:187–93

[6] Dietrich MO, Horvath TL. Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci 2013;36:65–73

[7] Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 2008;70:537–56

[8] Lee J, Liu J, Feng X, et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med 2016;22:1023–32

[9] Liu J, Lee J, Salazar Hernandez MA, et al. Treatment of obesity with celastrol. Cell 2015;161:999–1011

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

[11] Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011;377:557–67

[12] Scarpace PJ, Tumer N. Peripheral and hypothalamic leptin resistance with age-related obesity. Physiol Behav 2001;74:721–7

[13] Scarpace PJ, Matheny M, Moore RL, et al. Impaired leptin responsiveness in aged rats. Diabetes 2000;49:431–5

[14] Carter S, Caron A, Richard D, et al. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging 2013;8:829–44

[15] Chellappa K, Perron IJ, Naidoo N, et al. The leptin sensitizer celastrol reduces age-associated obesity and modulates behavioral rhythms. Aging Cell 2019;18:e12874

[16] St-Pierre J, Tremblay ML. Modulation of leptin resistance by protein tyrosine phosphatases. Cell Metab 2012;15:292–7

[17] Elchebly M, Payette P, Michaliszyn E, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999;283:1544–8

[18] Klaman LD, Boss O, Peroni OD, et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 2000;20:5479–89

[19] Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013;153:1194–217

[20] Gagarina V, Gabay O, Dvir-Ginzberg M, et al. SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway. Arthritis Rheum 2010;62:1383–92

[21] Sun C, Zhang F, Ge X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 2007;6:307–19

[22] Tiganis T. PTP1B and TCPTP—nonredundant phosphatases in insulin signaling and glucose homeostasis. FEBS J 2013;280:445–58

[23] Loh K, Fukushima A, Zhang X, et al. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 2011;14:684–99

[24] Zhang Z, Zhang H, Li B, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 2014;5:5493

[25] Dang Y, An Y, He J, et al. Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression. Aging Cell 2020;19:e13060

[26] Xia B, Shi XC, Xie BC, et al. Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice. PLoS Biol 2020;18:e3000688

[27] Ryu D, Mouchiroud L, Andreux PA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 2016;22:879–88

[28] Thang TD, Kuo PC, Yu CS, et al. Chemical constituents of the leaves of Glochidion obliquum and their bioactivity. Arch Pharm Res 2011;34:383–9

[29] He YF, Nan M-L, Sun J-M, et al. Synthesis, characterization and cytotoxicity of new rotundic acid derivatives. Molecules 2012;17:1278–91

[30] Zhu J et al. Prediction of drug efficacy from transcriptional profiles with deep learning. Nat Biotechnol 2021;39:1444–52

[31] Zahn JM et al. Transcriptional profiling of aging in human muscle reveals a common aging signature. PLoS Genet 2006;2:e115

[32] Xie Z et al. Molecular phenotyping of aging in single yeast cells using a novel microfluidic device. Aging Cell 2012;11:599–606

[33] WHO methods and data sources for country-level causes of death 2000–2019 (Global Health Estimates Technical Paper WHO/DDI/DNA/GHE/2020.2)

[34] Dalamaga M et al. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 2013;18:29–42

[35] Halaas JL et al. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci USA 1997;94:8878–83

[36] Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–70

[37] Bal NC et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 2012;18:1575–9

[38] Cypess AM et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509–17

[39] Keiser MJ et al. Relating protein pharmacology by ligand chemistry. Nat Biotechnol 2007;25:197–206

[40] Wiesmann C et al. Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol 2004;11:730–7

[41] Keedy DA et al. An expanded allosteric network in PTP1B by multi-temperature crystallography, fragment screening, and covalent tethering. Elife 2018;7:e36307

[42] Zabolotny JM et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell 2002;2:489–95

[43] Bence KK et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 2006;12:917–24

[44] Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol 2006;207:12–22

[45] Ghilardi N, Skoda RC. The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol Endocrinol 1997;11:393–9

[46] Vaisse C et al. Leptin activation of Stat3 in the hypothalamus of wildtype and ob/ob mice but not db/db mice. Nat Genet 1996;14:95–7

[47] Maheshwari N, Karthikeyan C, Trivedi P, et al. Recent advances in protein tyrosine phosphatase 1B targeted drug discovery for type II diabetes and obesity. Curr Drug Targets 2018;19:551–75

[48] Kyriakou E et al. Celastrol promotes weight loss in diet-induced obesity by inhibiting the protein tyrosine phosphatases PTP1B and TCPTP in the Hypothalamus. J Med Chem 2018;61:11144–57

[49] Yip SC, Saha S, Chernoff J. PTP1B: a double agent in metabolism and oncogenesis. Trends Biochem Sci 2010;35:442–9

[50] Xu H et al. Phosphatase PTP1B negatively regulates MyD88-and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol Immunol 2008;45:3545–52

[51] Le Sommer S et al. Deficiency in protein tyrosine phosphatase PTP1B shortens lifespan and leads to development of acute leukemia. Cancer Res 2018;78:75–87

[52] Dodd GT et al. Intranasal targeting of hypothalamic PTP1B and TCPTP reinstates leptin and insulin sensitivity and promotes weight loss in obesity. Cell Rep 2019;28:2905–2922.e2905

[53] Dodd GT et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 2015;160:88–104

[54] Garcia-San Frutos M et al. Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: effect of caloric restriction. Mech Ageing Dev 2012;133:489–97

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