Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Programming of metabolism by adipokines during development

Nature Reviews Endocrinology volume 19, pages 385–397 (2023)Cite this article

Subjects

Abstract

The intrauterine and early postnatal periods represent key developmental stages in which an organism is highly susceptible to being permanently influenced by maternal factors and nutritional status. Strong evidence indicates that either undernutrition or overnutrition during development can predispose individuals to disease later in life, especially type 2 diabetes mellitus and obesity, a concept known as metabolic programming. Adipose tissue produces important signalling molecules that control energy and glucose homeostasis, including leptin and adiponectin. In addition to their well-characterized metabolic effects in adults, adipokines have been associated with metabolic programming by affecting different aspects of development. Therefore, alterations in the secretion or signalling of adipokines, caused by nutritional insults in early life, might lead to metabolic diseases in adulthood. This Review summarizes and discusses the potential role of several adipokines in inducing metabolic programming through their effects during development. The identification of the endocrine factors that act in early life to permanently influence metabolism represents a key step in understanding the mechanisms behind metabolic programming. Thus, future strategies aiming to prevent and treat these metabolic diseases can be designed, taking into consideration the relationship between adipokines and the developmental origins of health and disease.

Key points

  • Undernutrition or overnutrition during critical developmental periods can alter the predisposition to metabolic diseases later in life, including type 2 diabetes mellitus and obesity, a concept known as metabolic programming.

  • Leptin and adiponectin are produced by adipocytes and in addition to their well-characterized metabolic effects in adults, these adipokines have been associated with metabolic programming by affecting different developmental aspects.

  • Maternal obesity, gestational diabetes mellitus and other metabolic imbalances during pregnancy affect the maternal circulating levels of leptin and adiponectin and the fetal exposure to these adipokines.

  • Early infancy represents a critical developmental period in which nutritional insults, associated with the action of adipokines, determine the risk of metabolic diseases later in life.

  • Leptin action in early life possibly programmes metabolism by controlling the development of hypothalamic neurocircuits, inducing permanent changes in the preference for hyper-palatable foods and decreasing energy expenditure.

  • Adiponectin effects in the mother and placenta regulate fetal exposure to nutrients and consequently fetal growth and/or nutrition, with long-term consequences for metabolism and predisposition to diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Environmental factors that potentially programme an organism to be more or less susceptible to disease in adulthood.
Fig. 2: Key milestones in the effects of leptin during the postnatal period in mice.
Fig. 3: Proposed mechanisms to explain the developmental effects of adiponectin.

Similar content being viewed by others

References

  1. Hales, C. N. & Barker, D. J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595–601 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Barker, D. J. & Osmond, C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1, 1077–1081 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Barker, D. J., Winter, P. D., Osmond, C., Margetts, B. & Simmonds, S. J. Weight in infancy and death from ischaemic heart disease. Lancet 2, 577–580 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Ravelli, A. C. et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351, 173–177 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Langley-Evans, S. C. Early life programming of health and disease: the long-term consequences of obesity in pregnancy. J. Hum. Nutr. Diet. 35, 816–832 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Saeedi, P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 157, 107843 (2019).

    Article  PubMed  Google Scholar 

  7. Morton, G. J., Meek, T. H. & Schwartz, M. W. Neurobiology of food intake in health and disease. Nat. Rev. Neurosci. 15, 367–378 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1, 1155–1161 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Masuzaki, H. et al. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat. Med. 3, 1029–1033 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Ramos-Lobo, A. M. & Donato, J. Jr. The role of leptin in health and disease. Temperature 4, 258–291 (2017).

    Article  Google Scholar 

  13. Andreoli, M. F., Donato, J., Cakir, I. & Perello, M. Leptin resensitisation: a reversion of leptin-resistant states. J. Endocrinol. 241, R81–R96 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Farooqi, I. S. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093–1103 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Licinio, J. et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc. Natl Acad. Sci. USA 101, 4531–4536 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Straub, L. G. & Scherer, P. E. Metabolic messengers: adiponectin. Nat. Metab. 1, 334–339 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Eriksson, J. G. et al. Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals. Diabetologia 45, 342–348 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Ozanne, S. E. Metabolic programming in animals. Br. Med. Bull. 60, 143–152 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Weiss, J. L. et al. Obesity, obstetric complications and cesarean delivery rate — a population-based screening study. Am. J. Obstet. Gynecol. 190, 1091–1097 (2004).

    Article  PubMed  Google Scholar 

  21. Leddy, M. A., Power, M. L. & Schulkin, J. The impact of maternal obesity on maternal and fetal health. Rev. Obstet. Gynecol. 1, 170–178 (2008).

    PubMed  PubMed Central  Google Scholar 

  22. Gilbert, J. A. The association of maternal obesity, large babies, and diabetes. Br. Med. J. 1, 702–704 (1949).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reynolds, R. M. et al. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. Br. Med. J. 347, f4539 (2013).

    Article  Google Scholar 

  24. Kral, J. G. et al. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Pediatrics 118, e1644–1649 (2006).

    Article  PubMed  Google Scholar 

  25. Inzani, I. & Ozanne, S. E. Programming by maternal obesity: a pathway to poor cardiometabolic health in the offspring. Proc. Nutr. Soc. 81, 227–242 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Boney, C. M., Verma, A., Tucker, R. & Vohr, B. R. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 115, e290–296 (2005).

    Article  PubMed  Google Scholar 

  27. Damm, P. et al. Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia 59, 1396–1399 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Steculorum, S. M. & Bouret, S. G. Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring. Endocrinology 152, 4171–4179 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rossner, S. Childhood obesity and adulthood consequences. Acta Paediatr. 87, 1–5 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Must, A. & Strauss, R. S. Risks and consequences of childhood and adolescent obesity. Int. J. Obes. Relat. Metab. Disord. 23, S2–11 (1999).

    Article  PubMed  Google Scholar 

  31. Glavas, M. M. et al. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. Endocrinology 151, 1598–1610 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vogt, M. C. et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156, 495–509 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sun, B. et al. Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity. Diabetes 61, 2833–2841 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rolls, B. A., Gurr, M. I., van Duijvenvoorde, P. M., Rolls, B. J. & Rowe, E. A. Lactation in lean and obese rats: effect of cafeteria feeding and of dietary obesity on milk composition. Physiol. Behav. 38, 185–190 (1986).

    Article  CAS  PubMed  Google Scholar 

  35. Kugananthan, S. et al. Associations between maternal body composition and appetite hormones and macronutrients in human milk. Nutrients 9, 252 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sinkiewicz-Darol, E., Adamczyk, I., Lubiech, K., Pilarska, G. & Twaruzek, M. Leptin in human milk — one of the key regulators of nutritional programming. Molecules 27, 3581 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mohamad, M. et al. Maternal serum and breast milk adiponectin: the association with infant adiposity development. Int. J. Environ. Res. Public Health 15, 1250 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Pena-Leon, V. et al. Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21. Nat. Metab. 4, 901–917 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lima Nda, S. et al. Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br. J. Nutr. 105, 1405–1413 (2011).

    Article  PubMed  Google Scholar 

  40. Jevitt, C., Hernandez, I. & Groer, M. Lactation complicated by overweight and obesity: supporting the mother and newborn. J. Midwifery Women’s Health 52, 606–613 (2007).

    Article  Google Scholar 

  41. Buonfiglio, D. C. et al. Obesity impairs lactation performance in mice by inducing prolactin resistance. Sci. Rep. 6, 22421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Malik, N. M. et al. Leptin expression in the fetus and placenta during mouse pregnancy. Placenta 26, 47–52 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Schubring, C. et al. Leptin serum concentrations in healthy neonates within the first week of life: relation to insulin and growth hormone levels, skinfold thickness, body mass index and weight. Clin. Endocrinol. 51, 199–204 (1999).

    Article  CAS  Google Scholar 

  44. Pighetti, M. et al. Maternal serum and umbilical cord blood leptin concentrations with fetal growth restriction. Obstet. Gynecol. 102, 535–543 (2003).

    CAS  PubMed  Google Scholar 

  45. Simpson, J. et al. Programming of adiposity in childhood and adolescence: associations with birth weight and cord blood adipokines. J. Clin. Endocrinol. Metab. 102, 499–506 (2017).

    PubMed  Google Scholar 

  46. Rifas-Shiman, S. L. et al. First and second trimester gestational weight gains are most strongly associated with cord blood levels of hormones at delivery important for glycemic control and somatic growth. Metabolism 69, 112–119 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huang, R. et al. Large-for-gestational-age, leptin, and adiponectin in infancy. J. Clin. Endocrinol. Metab. 107, e688–e697 (2022).

    Article  PubMed  Google Scholar 

  48. Karakosta, P. et al. Cord blood leptin levels in relation to child growth trajectories. Metabolism 65, 874–882 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Morris, M. J. & Chen, H. Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth. Int. J. Obes. 33, 115–122 (2008).

    Article  Google Scholar 

  50. Forhead, A. J. & Fowden, A. L. The hungry fetus? Role of leptin as a nutritional signal before birth. J. Physiol. 587, 1145–1152 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gupta, A., Srinivasan, M., Thamadilok, S. & Patel, M. S. Hypothalamic alterations in fetuses of high fat diet-fed obese female rats. J. Endocrinol. 200, 293–300 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Kirk, S. L. et al. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE 4, e5870 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Brynhildsen, J. et al. Leptin and adiponectin in cord blood from children of normal weight, overweight and obese mothers. Acta Paediatr. 102, 620–624 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Chen, H., Simar, D. & Morris, M. J. Hypothalamic neuroendocrine circuitry is programmed by maternal obesity: interaction with postnatal nutritional environment. PLoS ONE 4, e6259 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Lins, M. C., de Moura, E. G., Lisboa, P. C., Bonomo, I. T. & Passos, M. C. Effects of maternal leptin treatment during lactation on the body weight and leptin resistance of adult offspring. Regul. Pept. 127, 197–202 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Vitoratos, N. et al. Maternal plasma leptin levels and their relationship to insulin and glucose in gestational-onset diabetes. Gynecol. Obstet. Invest. 51, 17–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Qiu, C., Williams, M. A., Vadachkoria, S., Frederick, I. O. & Luthy, D. A. Increased maternal plasma leptin in early pregnancy and risk of gestational diabetes mellitus. Obstet. Gynecol. 103, 519–525 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Huvenne, H. et al. Seven novel deleterious LEPR mutations found in early-onset obesity: a Δexon6–8 shared by subjects from Reunion Island, France, suggests a founder effect. J. Clin. Endocrinol. Metab. 100, E757–766 (2015).

    Article  PubMed  Google Scholar 

  59. Caron, E., Sachot, C., Prevot, V. & Bouret, S. G. Distribution of leptin-sensitive cells in the postnatal and adult mouse brain. J. Comp. Neurol. 518, 459–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Teixeira, P. D. S. et al. Characterization of the onset of leptin effects on the regulation of energy balance. J. Endocrinol. 249, 239–251 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Bouret, S. G., Bates, S. H., Chen, S., Myers, M. G. Jr. & Simerly, R. B. Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. J. Neurosci. 32, 1244–1252 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mistry, A. M., Swick, A. & Romsos, D. R. Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice. Am. J. Physiol. 277, R742–R747 (1999).

    CAS  PubMed  Google Scholar 

  63. Ahima, R. S., Prabakaran, D. & Flier, J. S. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J. Clin. Invest. 101, 1020–1027 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Skowronski, A. A., Shaulson, E. D., Leibel, R. L. & LeDuc, C. A. The postnatal leptin surge in mice is variable in both time and intensity and reflects nutritional status. Int. J. Obes. 46, 39–49 (2022).

    Article  CAS  Google Scholar 

  65. Bouret, S. G., Draper, S. J. & Simerly, R. B. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J. Neurosci. 24, 2797–2805 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bouret, S. G., Draper, S. J. & Simerly, R. B. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Bouret, S. G. et al. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 7, 179–185 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lee, C. H. et al. Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus. Nat. Commun. 11, 5772 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wu, R. et al. Postnatal leptin surge is critical for the transient induction of the developmental beige adipocytes in mice. Am. J. Physiol. Endocrinol. Metab. 318, E453–E461 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yuen, B. S. et al. Leptin alters the structural and functional characteristics of adipose tissue before birth. FASEB J. 17, 1102–1104 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Yau-Qiu, Z. X., Madrid-Gambin, F., Brennan, L., Palou, A. & Rodriguez, A. M. Leptin supplementation during lactation restores key liver metabolite levels malprogrammed by gestational calorie restriction. Mol. Nutr. Food Res. 65, e2001046 (2021).

    Article  PubMed  Google Scholar 

  72. Samuelsson, A. M. et al. Experimental hyperleptinemia in neonatal rats leads to selective leptin responsiveness, hypertension, and altered myocardial function. Hypertension 62, 627–633 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Ramos-Lobo, A. M. et al. Long-term consequences of the absence of leptin signaling in early life. eLife 8, e40970 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Sominsky, L., Ziko, I., Nguyen, T. X., Quach, J. & Spencer, S. J. Hypothalamic effects of neonatal diet: reversible and only partially leptin dependent. J. Endocrinol. 234, 41–56 (2017).

    Article  PubMed  Google Scholar 

  75. Attig, L. et al. Early postnatal leptin blockage leads to a long-term leptin resistance and susceptibility to diet-induced obesity in rats. Int. J. Obes. 32, 1153–1160 (2008).

    Article  CAS  Google Scholar 

  76. Collden, G., Caron, E. & Bouret, S. G. Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice. Int. J. Obes. 46, 1138–1144 (2022).

    Article  CAS  Google Scholar 

  77. Vickers, M. H. et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 146, 4211–4216 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Skowronski, A. A. et al. Physiological consequences of transient hyperleptinemia during discrete developmental periods on body weight in mice. Sci. Transl. Med. 12, eaax6629 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Finger, B. C., Schellekens, H., Dinan, T. G. & Cryan, J. F. Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day. Psychopharmacology 216, 421–429 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Wasinski, F. et al. Growth hormone receptor deletion reduces the density of axonal projections from hypothalamic arcuate nucleus neurons. Neuroscience 434, 136–147 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Wasinski, F. et al. Ghrelin-induced food intake, but not GH secretion, requires the expression of the GH receptor in the brain of male mice. Endocrinology 162, bqab097 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Furigo, I. C. et al. Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. Nat. Commun. 10, 662 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cabral, A. et al. Fasting induces remodeling of the orexigenic projections from the arcuate nucleus to the hypothalamic paraventricular nucleus, in a growth hormone secretagogue receptor–dependent manner. Mol. Metab. 32, 69–84 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Ong, Z. Y., Gugusheff, J. R. & Muhlhausler, B. S. Perinatal overnutrition and the programming of food preferences: pathways and mechanisms. J. Dev. Orig. Health Dis. 3, 299–308 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Lagisz, M. et al. Transgenerational effects of caloric restriction on appetite: a meta-analysis. Obes. Rev. 15, 294–309 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Kelley, L., Verlezza, S., Long, H., Loka, M. & Walker, C. D. Increased hypothalamic projections to the lateral hypothalamus and responses to leptin in rat neonates from high fat fed mothers. Front. Neurosci. 13, 1454 (2019).

    Article  PubMed  Google Scholar 

  89. Leinninger, G. M. et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 14, 313–323 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zeltser, L. M. Feeding circuit development and early-life influences on future feeding behaviour. Nat. Rev. Neurosci. 19, 302–316 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pico, C., Jilkova, Z. M., Kus, V., Palou, A. & Kopecky, J. Perinatal programming of body weight control by leptin: putative roles of AMP kinase and muscle thermogenesis. Am. J. Clin. Nutr. 94, 1830S–1837S (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Mostyn, A. et al. Differential effects of leptin on thermoregulation and uncoupling protein abundance in the neonatal lamb. FASEB J. 16, 1438–1440 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Bouyer, K. & Simerly, R. B. Neonatal leptin exposure specifies innervation of presympathetic hypothalamic neurons and improves the metabolic status of leptin-deficient mice. J. Neurosci. 33, 840–851 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Stocker, C. J. et al. Prevention of diet-induced obesity and impaired glucose tolerance in rats following administration of leptin to their mothers. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1810–1818 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Schellong, K. et al. Hypothalamic insulin receptor expression and DNA promoter methylation are sex-specifically altered in adult offspring of high-fat diet (HFD)-overfed mother rats. J. Nutr. Biochem. 67, 28–35 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Keleher, M. R. et al. Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring. PLoS ONE 13, e0192606 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Berglind, D. et al. Differential methylation in inflammation and type 2 diabetes genes in siblings born before and after maternal bariatric surgery. Obesity 24, 250–261 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Lecoutre, S. et al. Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner. Mol. Metab. 6, 922–930 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Masuyama, H., Mitsui, T., Eguchi, T., Tamada, S. & Hiramatsu, Y. The effects of paternal high-fat diet exposure on offspring metabolism with epigenetic changes in the mouse adiponectin and leptin gene promoters. Am. J. Physiol. Endocrinol. Metab. 311, E236–245 (2016).

    Article  PubMed  Google Scholar 

  100. Jousse, C. et al. Perinatal undernutrition affects the methylation and expression of the leptin gene in adults: implication for the understanding of metabolic syndrome. FASEB J. 25, 3271–3278 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Mansell, T. et al. Methylation of the LEP gene promoter in blood at 12 months and BMI at 4 years of age — a population-based cohort study. Int. J. Obes. 44, 842–847 (2020).

    Article  CAS  Google Scholar 

  102. Xie, D. et al. TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons. J. Clin. Invest. 132, e162365 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kuhnen, P. et al. Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity. Cell Metab. 24, 502–509 (2016).

    Article  PubMed  Google Scholar 

  104. Benoit, C. et al. Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs. J. Endocrinol. 218, 35–47 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Palou, M. et al. Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene. Br. J. Nutr. 106, 769–778 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Derghal, A. et al. Leptin is required for hypothalamic regulation of miRNAs targeting POMC 3’UTR. Front. Cell Neurosci. 9, 172 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Aye, I. L. M. H., Powell, T. L. & Jansson, T. Review: adiponectin — the missing link between maternal adiposity, placental transport and fetal growth? Placenta 34, S40–S45 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Qiao, L. et al. Adiponectin enhances mouse fetal fat deposition. Diabetes 61, 3199–3207 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ategbo, J. M. et al. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. J. Clin. Endocrinol. Metab. 91, 4137–4143 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Caminos, J. E. et al. Expression and regulation of adiponectin and receptor in human and rat placenta. J. Clin. Endocrinol. Metab. 90, 4276–4286 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Lekva, T. et al. Large reduction in adiponectin during pregnancy is associated with large-for-gestational-age newborns. J. Clin. Endocrinol. Metab. 102, 2552–2559 (2017).

    Article  PubMed  Google Scholar 

  112. Jones, H. N., Jansson, T. & Powell, T. L. Full-length adiponectin attenuates insulin signaling and inhibits insulin-stimulated amino acid transport in human primary trophoblast cells. Diabetes 59, 1161–1170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Duval, F. et al. Adiponectin inhibits nutrient transporters and promotes apoptosis in human villous cytotrophoblasts: involvement in the control of fetal growth. Biol. Reprod. 94, 111 (2016).

    Article  PubMed  Google Scholar 

  114. Rosario, F. J. et al. Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth. J. Physiol. 590, 1495–1509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mohan Shrestha, M., Wermelin, S., Stener-Victorin, E., Wernstedt Asterholm, I. & Benrick, A. Adiponectin deficiency alters placenta function but does not affect fetal growth in mice. Int. J. Mol. Sci. 23, 4939 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Qiao, L. et al. Knockout maternal adiponectin increases fetal growth in mice: potential role for trophoblast IGFBP-1. Diabetologia 59, 2417–2425 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Aye, I. L., Rosario, F. J., Powell, T. L. & Jansson, T. Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc. Natl Acad. Sci. USA 112, 12858–12863 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Qiao, L. et al. Adiponectin promotes maternal β-cell expansion through placental lactogen expression. Diabetes 70, 132–142 (2021).

    Article  CAS  PubMed  Google Scholar 

  119. Corbetta, S. et al. Adiponectin expression in human fetal tissues during mid- and late gestation. J. Clin. Endocrinol. Metab. 90, 2397–2402 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Patel, N. et al. Cord metabolic profiles in obese pregnant women: insights into offspring growth and body composition. J. Clin. Endocrinol. Metab. 103, 346–355 (2018).

    Article  PubMed  Google Scholar 

  121. Mantzoros, C. S. et al. Cord blood leptin and adiponectin as predictors of adiposity in children at 3 years of age: a prospective cohort study. Pediatrics 123, 682–689 (2009).

    Article  PubMed  Google Scholar 

  122. Dumolt, J., Powell, T. L., Jansson, T. & Rosario, F. J. Normalization of maternal adiponectin in obese pregnant mice prevents programming of impaired glucose metabolism in adult offspring. FASEB J. 36, e22383 (2022).

    Article  CAS  PubMed  Google Scholar 

  123. Paulsen, M. E., Rosario, F. J., Wesolowski, S. R., Powell, T. L. & Jansson, T. Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring. FASEB J. 33, 2899–2909 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Yu, X. et al. Associations of breast milk adiponectin, leptin, insulin and ghrelin with maternal characteristics and early infant growth: a longitudinal study. Br. J. Nutr. 120, 1380–1387 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. van Rossem, L. et al. Does breast milk adiponectin affect BMI and cardio-metabolic markers in childhood? Br. J. Nutr. 121, 905–913 (2019).

    Article  PubMed  Google Scholar 

  126. Jin, Z. et al. Maternal adiponectin controls milk composition to prevent neonatal inflammation. Endocrinology 156, 1504–1513 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Li, C. et al. The role of apelin-APJ system in diabetes and obesity. Front. Endocrinol. 13, 820002 (2022).

    Article  Google Scholar 

  128. Mayeur, S. et al. Apelin controls fetal and neonatal glucose homeostasis and is altered by maternal undernutrition. Diabetes 65, 554–560 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Vaughan, O. R., Powell, T. L. & Jansson, T. Apelin is a novel regulator of human trophoblast amino acid transport. Am. J. Physiol. Endocrinol. Metab. 316, E810–E816 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hanssens, S. et al. Maternal obesity alters the apelinergic system at the feto-maternal interface. Placenta 39, 41–44 (2016).

    Article  CAS  PubMed  Google Scholar 

  131. Hanssens, S. et al. Maternal obesity reduces apelin level in cord blood without altering the placental apelin/elabela-APJ system. Placenta 128, 112–115 (2022).

    Article  CAS  PubMed  Google Scholar 

  132. Alizadeh Pahlavani, H. Possible roles of exercise and apelin against pregnancy complications. Front. Endocrinol. 13, 965167 (2022).

    Article  Google Scholar 

  133. Chae, S. A., Son, J. S., de Avila, J. M., Du, M. & Zhu, M. J. Maternal exercise improves epithelial development of fetal intestine by enhancing apelin signaling and oxidative metabolism. Am. J. Physiol. Regul. Integr. Comp. Physiol. 323, R728–R738 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Chae, S. A. et al. Exerkine apelin reverses obesity-associated placental dysfunction by accelerating mitochondrial biogenesis in mice. Am. J. Physiol. Endocrinol. Metab. 322, E467–E479 (2022).

    Article  CAS  PubMed  Google Scholar 

  135. Son, J. S. et al. Maternal exercise intergenerationally drives muscle-based thermogenesis via activation of apelin-AMPK signaling. EBioMedicine 76, 103842 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Son, J. S. et al. Maternal exercise via exerkine apelin enhances brown adipogenesis and prevents metabolic dysfunction in offspring mice. Sci. Adv. 6, eaaz0359 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Marousez, L. et al. Breast milk apelin level increases with maternal obesity and high-fat feeding during lactation. Int. J. Obes. 45, 1052–1060 (2021).

    Article  CAS  Google Scholar 

  138. Gutaj, P. et al. The role of the adipokines in the most common gestational complications. Int. J. Mol. Sci. 21, 9408 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Cortelazzi, D. et al. Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies. Clin. Endocrinol. 66, 447–453 (2007).

    Article  CAS  Google Scholar 

  140. Hu, S. M., Chen, M. S. & Tan, H. Z. Maternal serum level of resistin is associated with risk for gestational diabetes mellitus: a meta-analysis. World J. Clin. Cases 7, 585–599 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Jiang, S., Teague, A. M., Tryggestad, J. B., Lyons, T. J. & Chernausek, S. D. Fetal circulating human resistin increases in diabetes during pregnancy and impairs placental mitochondrial biogenesis. Mol. Med. 26, 76 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Poizat, G. et al. Maternal resistin predisposes offspring to hypothalamic inflammation and body weight gain. PLoS ONE 14, e0213267 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ilcol, Y. O., Hizli, Z. B. & Eroz, E. Resistin is present in human breast milk and it correlates with maternal hormonal status and serum level of C-reactive protein. Clin. Chem. Lab. Med. 46, 118–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Zhang, W. et al. Association between circulating visfatin and gestational diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol. 55, 1113–1120 (2018).

    Article  PubMed  Google Scholar 

  145. Bienertova-Vasku, J. et al. Visfatin is secreted into the breast milk and is correlated with weight changes of the infant after the birth. Diabetes Res. Clin. Pract. 96, 355–361 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Briana, D. D. et al. Role of visfatin, insulin-like growth factor-I and insulin in fetal growth. J. Perinat. Med. 35, 326–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  147. Sun, J. et al. Circulating apelin, chemerin and omentin levels in patients with gestational diabetes mellitus: a systematic review and meta-analysis. Lipids Health Dis. 19, 26 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Barker, G., Lim, R., Georgiou, H. M. & Lappas, M. Omentin-1 is decreased in maternal plasma, placenta and adipose tissue of women with pre-existing obesity. PLoS ONE 7, e42943 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Liu, Y., Gong, M., Liu, S., Pan, Y. & Huo, Y. Effects of blood glucose on vaspin secretion in patients with gestational diabetes mellitus. Gynecol. Endocrinol. 37, 221–224 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Lu, L., Li, C., Deng, J., Luo, J. & Huang, C. Maternal serum NGAL in the first trimester of pregnancy is a potential biomarker for the prediction of gestational diabetes mellitus. Front. Endocrinol. 13, 977254 (2022).

    Article  Google Scholar 

  151. Zhu, J. et al. Association of blood lipocalin-2 levels with gestational diabetes mellitus: a systematic review and meta-analysis. Horm. Metab. Res. 54, 677–685 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ruszala, M. et al. Novel biomolecules in the pathogenesis of gestational diabetes mellitus 2.0. Int. J. Mol. Sci. 23, 4364 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wu, P. et al. Serum Fetuin-A and risk of gestational diabetes mellitus: an observational study and mendelian randomization analysis. J. Clin. Endocrinol. Metab. 107, e3841–e3849 (2022).

    Article  PubMed  Google Scholar 

  154. An, X. et al. Overexpression of lipocalin 2 in PBX1-deficient decidual NK cells promotes inflammation at the maternal-fetal interface. Am. J. Reprod. Immunol. 89, e13676 (2023).

    Article  CAS  PubMed  Google Scholar 

  155. Wang, W. J. et al. Fetuin-A in infants born small- or large-for-gestational-age. Front. Endocrinol. 11, 567955 (2020).

    Article  Google Scholar 

  156. Tan, L. et al. Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms. Clin. Sci. 136, 257–272 (2022).

    Article  CAS  Google Scholar 

  157. Gopalakrishnan, K., Mishra, J. S., Ross, J. R., Abbott, D. H. & Kumar, S. Hyperandrogenism diminishes maternal–fetal fatty acid transport by increasing FABP4-mediated placental lipid accumulation. Biol. Reprod. 107, 514–528 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  158. de Luca, C. et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J. Clin. Invest. 115, 3484–3493 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Xu, J. et al. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chen, J. et al. Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines. Diabetologia 49, 1292–1302 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

J.D. acknowledges the support of the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-Brazil; grant number: 2020/01318–8). J.D. also thanks M. Metzger (University of São Paulo) and F. Wasinski (Federal University of São Paulo) for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

    Jose Donato Jr

Authors
  1. Jose Donato Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose Donato Jr.

Ethics declarations

Competing interests

The author declares no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Manuel Tena-Sempere and the other, anonymous, reviewer(s) 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

Obesity: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

T2DM: https://www.who.int/news-room/fact-sheets/detail/diabetes

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Donato, J. Programming of metabolism by adipokines during development. Nat Rev Endocrinol 19, 385–397 (2023). https://doi.org/10.1038/s41574-023-00828-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-023-00828-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing