Testing the leanocentric locking-point theory by in silico partial lipectomy

Abstract

Background: The lipostatic set-point theory, ascribing fat mass homeostasis to leptin mediated central feedback regulation targeting the body’s fat storage, has caused a variety of conundrums. We recently proposed a leanocentric locking-point theory and the corresponding mathematical model, which not only resolve these conundrums but also provide valuable insights into weight control and health assessment. This paper aims to further test the leanocentric theory.

Methods: Partial lipectomy is a touchstone to test both the leanocentric and lipostatic theories. Here we perform in silico lipectomy by using a mathematical model embodying the leanocentric theory to simulate the long-term body fat change after removing some fat cells in the body.

Results: The mathematical modeling uncovers a phenomenon called post-surgical fat loss, which was well-documented in real partial lipectomy surgeries; thus, the phenomenon can serve as an empirical support to the leanocentric theory. On the other hand, the leanocentric theory, but not the lipostatic theory, can well explain the post-surgical fat loss.

Conclusions: The leanocentric locking-point theory is a promising theory and deserves further testing. Partial lipectomy surgeries are beneficial to obese patients for quite a long period.

Keywords

leanocentric locking-point theory / lipostatic set-point theory / weight stability / fat mass homeostasis / partial lipectomy

References

[1] Neumann, R. O. (1902)Experimentelle beiträge zur lehre von dem täglichen nahrungsbedarf des menschen unter besonderer berück-sichtigung der notwendigen eiweissmenge. Arc. Hyg., 45, 1–87

[2] DuBois, E. F. (1924)Basal metabolism in health and disease. AGRIS

[3] Sims, E. A. and Horton, E. S. (1968) Endocrine and metabolic adaptation to obesity and starvation. Am. J. Clin. Nutr., 21, 1455–1470

[4] Passmore, R. (1971) The regulation of body-weight in man. Proc. Nutr. Soc., 30, 122–127

[5] Salans, L. B., Horton, E. S. and Sims, E. A. (1971) Experimental obesity in man: cellular character of the adipose tissue. J. Clin. Invest., 50, 1005–1011

[6] Mitchel, J. S. and Keesey, R. E. (1977) Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: evidence from a restriction-refeeding regimen. Physiol. Behav., 18, 1121–1125

[7] Rothwell, N. J. and Stock, M. J. (1979) Regulation of energy balance in two models of reversible obesity in the rat. J. Comp. Physiol. Psychol., 93, 1024–1034

[8] Leibel, R. L. and Hirsch, J. (1984) Diminished energy requirements in reduced-obese patients. Metabolism, 33, 164–170

[9] Leibel, R. L., Rosenbaum, M. and Hirsch, J. (1995) Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med., 332, 621–628

[10] Leibel, R. L. (2008) Molecular physiology of weight regulation in mice and humans. Int. J. Obes., 32, S98–S108

[11] Ravussin, Y., Leibel, R. L. and Ferrante, A. W. Jr. (2014) A missing link in body weight homeostasis: the catabolic signal of the overfed state. Cell Metab., 20, 565–572

[12] Rosenbaum, M. and Leibel, R. L. (2016) Models of energy homeostasis in response to maintenance of reduced body weight. Obesity (Silver Spring), 24, 1620–1629

[13] Kennedy, G. C. (1953) The role of depot fat in the hypothalamic control of food intake in the rat. Proc. R. Soc. Lond. B Biol. Sci., 140, 578–592

[14] Anand, B. K. and Brobeck, J. R. (1951) Hypothalamic control of food intake in rats and cats. Yale J. Biol. Med., 24, 123–140

[15] Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J. M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature, 372, 425–432

[16] Leibel, R. L. (1997) And finally, genes for human obesity. Nat. Genet., 16, 218–220

[17] Friedman, J. M. and Halaas, J. L. (1998) Leptin and the regulation of body weight in mammals. Nature, 395, 763–770

[18] Rosenbaum, M. and Leibel, R. L. (1999) The role of leptin in human physiology. N. Engl. J. Med., 341, 913–915

[19] Schwartz, M. W., Woods, S. C., Porte, D. Jr, Seeley, R. J. and Baskin, D. G. (2000) Central nervous system control of food intake. Nature, 404, 661–671

[20] Myers, M. G. Jr, Münzberg, H., Leinninger, G. M. and Leshan, R. L. (2009) The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab., 9, 117–123

[21] Rosenbaum, M. and Leibel, R. L. (2014) 20 years of leptin: role of leptin in energy homeostasis in humans. J. Endocrinol., 223, T83–T96

[22] Müller, M. J., Geisler, C., Heymsfield, S. B. and Bosy-Westphal, A. (2018) Recent advances in understanding body weight homeostasis in humans. F1000 Res., 7, 7

[23] Cohen, S. L., Halaas, J. L., Friedman, J. M., Chait, B. T., Bennett, L., Chang, D., Hecht, R. and Collins, F. (1996) Human leptin characterization. Nature, 382, 589

[24] Halaas, J. L., Boozer, C., Blair-West, J., Fidahusein, N., Denton, D. A. and Friedman, J. M. (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl. Acad. Sci. USA, 94, 8878–8883

[25] Harris, R. B., Hausman, D. B. and Bartness, T. J. (2002) Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes. Am. J. Physiol. Regul. Integr. Comp. Physiol., 283, R1094–R1103

[26] Zeng, W., Lu, Y.-H., Lee, J. and Friedman, J. M. (2015) Reanalysis of parabiosis of obesity mutants in the age of leptin. Proc. Natl. Acad. Sci. USA, 112, E3874–E3882

[27] Ravussin, Y., Edwin, E., Gallop, M., Xu, L., Bartolomé, A., Kraakman, M. J., LeDuc, C. A. and Ferrante, A. W. Jr. (2018) Evidence for a non-leptin system that defends against weight gain in overfeeding. Cell Metab., 28, 289–299.e5

[28] Wang, G. (2020) Body mass dynamics is determined by the metabolic ohms law and adipocyteautonomous fat mass homeostasis. IScience,23, 101176

[29] Speakman, J. R. (2018) Why lipostatic set point systems are unlikely to evolve. Mol. Metab., 7, 147–154

[30] Perello, M., Scott, M. M., Sakata, I., Lee, C. E., Chuang, J.-C., Osborne-Lawrence, S., Rovinsky, S. A., Elmquist, J. K. and Zigman, J. M. (2012) Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. J. Comp. Neurol., 520, 281–294

[31] Davis, D. A., Pellowski, D. M., Davis, D. A. and Donahoo, W. T. (2006) Acute and 1-month effect of small-volume suction lipectomy on insulin sensitivity and cardiovascular risk. Int. J. Obes., 30, 1217–1222

[32] Kral, J. G. (1976) Surgical reduction of adipose tissue in the male Sprague-Dawley rat. Am. J. Physiol., 231, 1090–1096

[33] Hernandez, T. L., Kittelson, J. M., Law, C. K., Ketch, L. L., Stob, N. R., Lindstrom, R. C., Scherzinger, A., Stamm, E. R. and Eckel, R. H. (2011) Fat redistribution following suction lipectomy: defense of body fat and patterns of restoration. Obesity (Silver Spring), 19, 1388–1395

[34] Michel, C. and Cabanac, M. (1999) Lipectomy, body weight, and body weight set point in rats. Physiol. Behav., 66, 473–479

[35] Giese, S. Y., Bulan, E. J., Commons, G. W., Spear, S. L. and Yanovski, J. A. (2001) Improvements in cardiovascular risk profile with large-volume liposuction: a pilot study. Plast. Reconstr. Surg., 108, 510–519., discussion 520–521.

[36] Giese, S. Y., Neborsky, R., Bulan, E. J., Spear, S. L. and Yanovski, J. A. (2001) Improvements in cardiovascular risk profile after large-volume lipoplasty: a 1-year follow-up study. Aesthet. Surg. J., 21, 527–531

[37] Crahay, F. and Nizet, J. (2016) Metabolic and Cardiovascular Consequences of Suction-assisted Lipectomy: Systematic Review. In Annales de chirurgie plastique et esthetique, vol. 61270–286

[38] Andrew, M. S., Huffman, D. M., Rodriguez-Ayala, E., Williams, N. N., Peterson, R. M. and Bastarrachea, R. A. (2018) Mesenteric visceral lipectomy using tissue liquefaction technology reverses insulin resistance and causes weight loss in baboons. Surg. Obes. Relat. Dis., 14, 833–841

[39] Faust, I. M., Johnson, P. R. and Hirsch, J. (1976) Noncompensation of adipose mass in partially lipectomized mice and rats. Americ. J. Phys.Legac. Cont., 231, 538–544

[40] Swanson, E. (2012) Photographic measurements in 301 cases of liposuction and abdominoplasty reveal fat reduction without redistribution Plast. Reconstr. Surg. T., 130, 311e–322e

[41] Faust, I. M., Johnson, P. R. and Hirsch, J. (1977) Adipose tissue regeneration following lipectomy. Science, 197, 391–393

[42] Hausman, D. B., Lu, J., Ryan, D. H., Flatt, W. P. and Harris, R. B. (2004) Compensatory growth of adipose tissue after partial lipectomy: involvement of serum factors. Exp. Biol. Med. (Maywood), 229, 512–520

[43] Mauer, M. M., Harris, R. B. and Bartness, T. J. (2001) The regulation of total body fat: lessons learned from lipectomy studies. Neurosci. Biobehav. Rev., 25, 15–28

[44] Spalding, K. L., Arner, E., Westermark, P. O., Bernard, S., Buchholz, B. A., Bergmann, O., Blomqvist, L., Hoffstedt, J., Näslund, E., Britton, T., (2008) Dynamics of fat cell turnover in humans. Nature, 453, 783–787

[45] Matsuda, N., Hironaka, K.-i., Fujii, M., Wada, T., Kunida, K., Inoue, H., Eto, M., Hoshino, D., Furuichi, Y., Manabe, Y., (2020) Monitoring and mathematical modeling of mitochondrial atp in myotubes at single-cell level reveals two distinct population with different kinetics. Quant. Biol., 8, 228–237

[46] Chen, L., Liu, R., Liu, Z.-P., Li, M. and Aihara, K. (2012) Detecting early-warning signals for sudden deterioration of complex diseases by dynamical network biomarkers. Sci. Rep., 2, 342

[47] Wang, P. and Chen, L. (2020) Critical transitions and tipping points in EMT. Quant. Biol., 8, 195–202

[48] Wang, G. (2010)Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases Phys. Biol., 7, 046015

[49] Wang, G. (2012) Optimal homeostasis necessitates bistable control. J. R. Soc. Interface, 9, 2723–2734

[50] Li, T. and Wang, G. (2014)Computer-aided targeting of the PI3K/Akt/mTOR pathway: Toxicity reduction and therapeutic opportunities. Int. J. Mol. Sci. 15, 18856–18891

[51] Bonadonna, R. C., Leif, G., Kraemer, N., Ferrannini, E., Prato, S. D. and DeFronzo, R. A. (1990) Obesity and insulin resistance in humans: a dose-response study. Metabolism, 39, 452–459

[52] Havel, R. J., Naimark, A. and Borchgrevink, C. F. (1963) Turnover rate and oxidation of free fatty acids of blood plasma in man during exercise: studies during continuous infusion of palmitate-1-C14. J. Clin. Invest., 42, 1054–1063

[53] Polonsky, K. S., Given, B. D. and Van Cauter, E. (1988) Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J. Clin. Invest., 81, 442–448

[54] Wang, G. 2014 Raison dêtre of insulin resistance: the adjustable threshold hypothesis. J. R. Soc. Interface.11, 20140 892

[55] Bonadonna, R. C., Saccomani, M. P., Cobelli, C. and DeFronzo, R. A. (1993) Effect of insulin on system A amino acid transport in human skeletal muscle. J. Clin. Invest., 91, 514–521

[56] Lee, L. (1998)Volume of blood in a human. The Physics Factbook

[57] Hall, K. D. (2006) Computational model of in vivo human energy metabolism during semistarvation and refeeding. Am. J. Physiol. Endocrinol. Metab., 291, E23–E37

[58] Stumvoll, M., Jacob, S., Wahl, H. G., Hauer, B., Löblein, K., Grauer, P., Becker, R., Nielsen, M., Renn, W. and Häring, H. (2000) Suppression of systemic, intramuscular, and subcutaneous adipose tissue lipolysis by insulin in humans. J. Clin. Endocrinol. Metab., 85, 3740–3745

ACKNOWLEDGMENTS

This work was partly supported by the National Natural Science Foundation of China (Nos. 61773196 and 32070681), 2019 Key Projects of Ministry of Science and Technology of China (No. 2019YFA09006000), Guangdong Provincial Key Laboratory of Computational Science and Material Design (No. 2019B030301001), and Shenzhen Research Funds (No. JCYJ20170817104740861), Shenzhen Peacock Plan (No. KQTD2016053117035204), and by Center for Computational Science and Engineering of Southern University of Science and Technology.

COMPLIANCE WITH ETHICS GUIDELINES

The author Guanyu Wang declare that they have no conflict of interests.

This article does not contain any studies with human or animal subjects performed by the authors.

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