Leptin is a hormone that keeps us healthy in many ways. It regulates our body weight by reining in our appetite and fine-tuning the energy we burn, and it helps us establish and maintain our fertility. It also participates in brain development. Leptin performs these roles by attaching to specific receptors in nerve cells and relaying relevant information to the brain.

Early events can trigger life-long changes in the way our body works, a process called metabolic programming. Leptin is believed to participate in this reprogramming mechanism, but its role remains uncertain. In particular, it is still unclear which leptin-driven changes are permanent, and which ones are reversible. Being able to distinguish between the two types of alterations would help to better grasp the role leptin plays in early development.

Here, Ramos-Lobo et al. examined genetically engineered mice born without a working leptin receptor. These animals were impervious to the effects of leptin. Then, once the rodents were adults, they were treated with a drug that restored their leptin receptors, making them sensitive to the hormone again. These experiments revealed that mice without leptin receptors during early life developed obesity, were less able to lose weight and burned less energy. Their reproductive success was also compromised. Finally, the lack of leptin during development caused permanent reduction of the animals’ brains, and changes in the activity of certain genes in the organ.

The work by Ramos-Lobo et al. indicates that in mice, lacking leptin sensibility early in life conditions the body to permanently become ‘thrifty’, burning less energy and making it harder to lose weight. It is rare for humans to be born completely without leptin activity. Yet, having too much or too little food as a baby affects the level of the hormone, or our sensitivity to it: this may permanently change the way our bodies manage energy. Ultimately, learning more about these mechanisms could help us ward off or treat obesity.

The hormone leptin is best known as a key signal to the brain conveying information about body energy reserves (Maffei et al., 1995). Consequently, leptin receptor (LepR)-expressing neurons are apt to modulate food intake and energy expenditure according to the amount of energy stored and the current energy balance (Ramos-Lobo and Donato, 2017). Hence, null mutations in the genes that encode for leptin or LepR impair the capacity of the hypothalamus to regulate energy homeostasis, leading to profound metabolic dysfunctions in humans and rodents, including severe obesity, hyperphagia, low-energy expenditure, hypoactivity, insulin resistance and infertility (Halaas et al., 1995; Montague et al., 1997; Farooqi et al., 2002; Licinio et al., 2004).

In addition to the role of leptin in energy homeostasis, other studies have shown that leptin can affect developmental processes, especially in the brain (Ahima et al., 1999). Regarding this aspect, rodents exhibit a postnatal leptin surge between the first and second week of age that is not associated to changes in fat mass or food intake (Ahima et al., 1998). In addition, 2-week-old mice do not respond to the anorexigenic effects of leptin (Mistry et al., 1999). Thus, leptin does not seem to be involved in the regulation of energy balance during the first weeks of life in mice. However, synaptic plasticity in the hypothalamus is regulated by leptin (Pinto et al., 2004). Leptin signaling is also required for the formation of the neural projections from the arcuate nucleus (ARH) to post-synaptic targets, a process that takes place in the first 2 weeks of life (Bouret et al., 2004a; Kamitakahara et al., 2018). In accordance, leptin promotes neurite outgrowth in vitro and leptin-deficient (Lep^ob/ob) mice show disruption of ARH neural projections (Bouret et al., 2004b). Importantly, exogenous leptin rescues the development of ARH projections of Lep^ob/ob mice only when provided in the neonatal period. Thus, these findings suggest that the lack of leptin signaling in the first weeks of life permanently disrupts these projections in mice (Bouret et al., 2004b).

Important implications arise from the developmental effects of leptin. For example, changes in leptin signaling during development could then affect the organization of critical neural circuits that regulate energy homeostasis, favoring the incidence of metabolic diseases later in life. Thus, leptin may also be involved in the developmental programming (Ralevski and Horvath, 2015). Accordingly, early postnatal leptin blockage in rats leads to long-term leptin resistance and susceptibility to diet-induced obesity (Attig et al., 2008). Furthermore, neonatal leptin treatment reverses the developmental programming caused by maternal undernutrition (Vickers et al., 2005). However, it is worth mentioning that despite the aforementioned evidence about leptin’s developmental effects, exogenous leptin replacement can reverse key metabolic abnormalities exhibited by leptin-deficient mice or humans (Pelleymounter et al., 1995; Ioffe et al., 1998; Farooqi et al., 2002; Licinio et al., 2004; Donato et al., 2011). Therefore, the actual importance of leptin signaling during development for the long-term energy homeostasis and other aspects regulated by leptin is not yet fully understood. Thus, to uncover the role of leptin during development, we investigated the long-term consequences of the absence of leptin signaling in early life. For this purpose, we studied knockout mice for the Lepr gene that grew without leptin’s effects. However, LepR expression was restored either at the fourth or tenth week of life. Our findings revealed that some defects previously considered irreversible due to the lack of leptin signaling in the neonatal period, such as the poor development of ARH neural projections, can be recovered by LepR reactivation in adulthood. On the other hand, the absence of leptin signaling in early life permanently impairs energy homeostasis, the melanocortin system, as well as the reproduction and brain development.

Previous studies have shown evidence that defects in leptin signaling in early life can produce permanent consequences in brain development and energy homeostasis (Ahima et al., 1999; Bouret et al., 2004b; Vickers et al., 2005; Attig et al., 2008; Kamitakahara et al., 2018). On the other hand, the capacity of leptin to restore the dysfunctions of adult humans and mice previously deficient of this hormone could indicate that the action of leptin during development is not quite necessary, otherwise important sequelae should be observed despite leptin replacement (Pelleymounter et al., 1995; Ioffe et al., 1998; Farooqi et al., 2002; Licinio et al., 2004; Donato et al., 2011). Therefore, the exact importance of leptin signaling during development for the long-term homeostasis has not yet been fully revealed. To uncover the role of leptin during development, we studied a mouse model that grew without leptin’s effects until the fourth or tenth week of life. After LepR reactivation, Ubi-LepRNull mice completely recovered their capacity to respond to leptin by exhibiting the well-known anorexigenic effect of leptin and presenting STAT3 phosphorylation in key hypothalamic nuclei after an acute leptin injection. These results are in contrast to the leptin resistance produced by early postnatal infusion of a leptin antagonist (Attig et al., 2008). However, adult Lep^ob/ob mice show no indication of leptin resistance since acute or chronic leptin administration produces similar responses compared to lean animals (Halaas et al., 1995; Pelleymounter et al., 1995; Donato et al., 2011). Thus, our findings support the idea that the lack of leptin signaling during early life does not cause leptin resistance per se in adulthood.

Despite the functional evidence that leptin responsiveness was restored in Ubi-LepRNull mice, we cannot guarantee that leptin signaling was restored in all cells that normally express LepR. Since an incomplete reactivation of LepR could lead to some defects observed in Ubi-LepRNull mice, this could be a potential issue in our model. In mice that underwent tamoxifen treatment at 10 weeks of age, we observed a tendency towards a lower hypothalamic Lepr-b mRNA expression compared to Ubi animals. However, it is important to mention that Ubi-LepRNull mice were hyperleptinemic, compared to lean controls, and several studies have shown that chronic hyperleptinemia can downregulate Lepr expression in the hypothalamus (Martin et al., 2000; Ladyman and Grattan, 2005; Zhai et al., 2018). In accordance with this hypothesis, Lepr-b mRNA expression was completely restored in mice that underwent tamoxifen treatment at 4 weeks of age and did not become hyperleptinemic later in life, suggesting that the trend toward a lower Lepr-b mRNA expression in adult Ubi-LepRNull mice might be due to hyperleptinemia and not to insufficient reactivation of LepR.

Even though leptin responsiveness was recovered, Ubi-LepRNull mice still maintained a higher body weight, adiposity and serum leptin levels, compared to lean littermates. The increased body adiposity of Ubi-LepRNull mice was associated with their incapacity to normalize energy expenditure. Of note, weight loss increases energy efficiency and reduces energy expenditure beyond what is expected for the body mass loss (Leibel et al., 1995). Thus, to rule out a possible effect of weight loss in the metabolic dysfunctions exhibited by Ubi-LepRNull mice, we also induced the LepR reactivation in young animals, before they became obese. Since a higher body adiposity and suppressed energy expenditure were still present in those mice, our findings provide strong evidence that leptin signaling in early life is indeed required for the long-term energy homeostasis.

To further evaluate the energy homeostasis, the animals were exposed to opposing conditions of negative- and positive-energy balance. During fasting, both LepRNull and Ubi-LepRNull mice exhibited reduced drop in energy expenditure and lower rate of body weight loss. These results suggest a decreased capacity to lose weight in mice that grew without leptin signaling until adulthood. Thus, our findings are in accordance with the metabolic programming (Samuelsson et al., 2008), in which altered leptin signaling in early life may predispose adult individuals to metabolic diseases, such as obesity. LepRNull and Ubi-LepRNull mice also showed higher HFD intake, compared to lean controls. Since LepR reactivation completely normalized the intake of a low-fat diet, this observation indicates that the absence of leptin signaling in early life favors the consumption of a highly palatable/caloric diets. In fact, previous studies have shown that brain leptin signaling modulates the sensitivity to highly palatable food (Hommel et al., 2006). Therefore, our findings provide additional evidence about this effect, suggesting that disruption of leptin signaling during early life is sufficient to change the response in adulthood to palatable diets.

To uncover possible mechanisms by which the absence of leptin signaling during development caused long-term metabolic consequences, we evaluated the expression of mRNAs for key neuropeptides that regulate the energy balance. While the hypothalamic expression of orexigenic peptides, such as AgRP and NPY, were recovered in Ubi-LepRNull mice, LepR reactivation was unable to restore the mRNA levels of Pomc, Cartptand Prlh. Of note, leptin signaling in POMC/CART neurons or in hypothalamic Prlh cells influences the energy balance predominantly via changes in energy expenditure and not through food intake (Berglund et al., 2012; Dodd et al., 2014). Therefore, the mild obesity and lower metabolic rate of Ubi-LepRNull mice are likely associated with defects in POMC or Prlh neurons. Interestingly, previous studies have shown that the absence of hypothalamic POMC expression in early life also causes long-term metabolic imbalances, even though POMC expression is rescued in adulthood (Bumaschny et al., 2012; Chhabra et al., 2016). However, differently than Ubi-LepRNull mice, early POMC deficiency leads to increased food intake later in life. In addition, if POMC reactivation was induced in non-obese animals or at the fourth week of life, no metabolic imbalances were observed in adulthood (Bumaschny et al., 2012; Chhabra et al., 2016). In the case of LepR reactivation on the fourth week of life, we still observed a higher body adiposity and lower energy expenditure in Ubi-LepRNull mice, compared to lean controls.

HDAC proteins can produce epigenetic modifications via histone deacetylation and chromatin remodeling (Haberland et al., 2009). In addition, recent evidence indicates that HDAC5 regulates energy homeostasis via hypothalamic neurons (Kabra et al., 2016). Importantly, HDAC5 induces site-specific acetylation changes in POMC neurons and knockdown of hypothalamic Hdac5 suppresses Pomc mRNA levels in adult rats or mice, without affecting Agrp expression (Kabra et al., 2016). Since hypothalamic expression of Hdac3 and Hdac5 were not restored after LepR reactivation, histone-mediated epigenetic modifications in POMC neurons could be involved with the energy imbalance caused by the absence of leptin signaling in early life. The lack of leptin signaling during development may also have produced epigenetic changes via DNA methyltransferases, since hypothalamic Dnmt3a and Dnmt3b expression remained suppressed in Ubi-LepRNull mice. Accordingly, Dnmt3a ablation in PVH neurons causes obesity and decreased energy expenditure in mice (Kohno et al., 2014). However, whether epigenetic changes were indeed responsible for the metabolic dysfunctions of Ubi-LepRNull mice will require additional studies.

Previous reports have shown that metabolic imbalances during development alter insulin signaling in adulthood (Chen et al., 2009; Vogt et al., 2014). We observed that LepR reactivation in adult animals caused insulin resistance, without impairing glucose tolerance of Ubi-LepRNull mice. Since obesity leads to pancreatic beta cell hyperplasia (Bock et al., 2003), the normal glucose tolerance of Ubi-LepRNull mice could be explained by an obesity-induced increase in insulin secretory capacity, overcoming their insulin resistance. In contrast, LepR reactivation before the onset of obesity possibly prevented major pancreatic islet changes. Therefore, glucose homeostasis in our experimental animals was predominantly affected by the former obesity rather than by the absence of leptin signaling during development.

Leptin deficiency causes hypogonadotropic hypogonadism, low testicle weight, anestrus and infertility (Chehab et al., 1996; Mounzih et al., 1997; Farooqi et al., 2002; Licinio et al., 2004). LepR reactivation in adult animals was not sufficient to completely recover the reproductive system in both genders. However, leptin treatment rescues the sterility of male and female Lep^ob/ob mice (Chehab et al., 1996; Mounzih et al., 1997; Donato et al., 2011). The reasons of these contrasting results are unknown, but may be related to genetic differences between Lep^ob/ob and LepRNull mice or to the age at which the animals were studied. In the present study, the reproductive system was evaluated in 6- to 8-month-old animals, which is an older age to assess fertility than usual. This advanced age may explain why only half of females breeding with Ubi mice got pregnant. The alterations in reproduction observed in Ubi-LepRNull mice probably had a central cause since reductions in Kiss1 and Nos1 mRNA levels were observed in their hypothalami. These transcripts produce neurotransmitters that stimulate GnRH release (Messager et al., 2005; Bellefontaine et al., 2014). As a result, hypothalamic GnRH fiber density was not different between LepRNull and Ubi-LepRNull mice, indicating defects in the capacity to release GnRH in the hypophyseal portal system (Polkowska et al., 2006; Donato et al., 2011). Thus, our findings suggest that the absence of leptin signaling during development causes long-term defects in the neurocircuits that regulate the hypothalamic-pituitary-gonadal axis.

In adult animals, leptin responsive neurons are mostly confined to hypothalamic and brainstem nuclei involved in feeding and neuroendocrine regulation (Ramos-Lobo and Donato, 2017). However, during early postnatal life, Lepr mRNA expression is also detected in other brain regions, including the cerebral cortex, hippocampus and thalamus, suggesting a potential role of leptin in brain development (Caron et al., 2010). In this sense, we confirmed the results of previous studies indicating that leptin deficiency leads to reduced brain mass (Ahima et al., 1999). Interestingly, we also observed a sexually dimorphic response when LepR reactivation occurred in 4-week-old mice. In this case, Ubi-LepRNull females completely recovered their brain mass, whereas Ubi-LepRNull males exhibited a partial increase. Ahima et al., 1999 studied only female Lep^ob/ob mice and showed a greater recovery in brain mass when leptin replacement started at 4 weeks of life, compared with a later treatment. Therefore, males and females may present distinct critical postnatal periods, in which leptin acts in order to allow a normal brain development. The remarkable increase in brain mass after LepR reactivation can be explained by an increase in cell number and/or edema. Previous studies have shown conflicting results regarding the causes of the reduced brain mass in Lep^ob/ob mice. While some authors found reduced DNA content in the brain of Lep^ob/ob mice, indicating lower number of cells (van der Kroon and Speijers, 1979), other studies showed decreased soma cross-sectional area in neurons of Lep^ob/ob mice compared to controls (Bereiter and Jeanrenaud, 1979). Furthermore, Lep^ob/ob and wild-type mice exhibit similar brain protein content (Sena et al., 1985). Therefore, additional experiments are still necessary to investigate the possible mechanisms behind the increase in brain mass after LepR reactivation. Despite the reduction in brain mass, no evidence of behavioral or memory deficit was found in mice that grew without leptin signaling until adulthood. In humans, leptin replacement in a 5-year-old leptin-deficient boy rescued the cognitive development which was slower than expected for his age (Paz-Filho et al., 2008).

Our results are in accordance with earlier studies indicating that the absence of leptin signaling disrupts the normal developmental pattern of projections from the ARH to the PVH (Bouret et al., 2004b; Bouret et al., 2004a). However, an unexpected finding was the recovery of the density of AgRP and POMC fibers in the PVH of Ubi-LepRNull mice, even though the restoration of leptin signaling was induced several weeks after the previously indicated critical period for the trophic action of leptin (Bouret et al., 2004b; Kamitakahara et al., 2018). In our study, these projections were investigated by staining AgRP or POMC-derived peptides, which not necessarily allow the complete visualization of ARH neuron axons. So, it is uncertain whether LepR reactivation promoted axon extension into the PVH or just improved the visualization of processes that were already there. However, Bouret et al. (2004b) used the anterograde tracer DiI to demonstrate that this neurocircuit does not fully develop without leptin signaling. Additionally, we found a significant reduction in the amount of axons from LepR-expressing neurons in the PVH of Lep^ob/ob mice compared to control animals. Thus, these findings suggest that the higher density of AgRP and POMC fibers in the PVH after LepR restoration was likely caused by axonal growth.

The reasons for the divergent findings between our study and previous reports that indicated a critical postnatal period for the trophic action of leptin (Bouret et al., 2004b; Kamitakahara et al., 2018) are unknown, but may be related to methodological differences. While previous studies investigated the neurotrophic actions of leptin via repeated injections in Lep^ob/ob mice (Bouret et al., 2004b; Kamitakahara et al., 2018), our study allowed the endogenously produced leptin to act in a physiological manner. Thus, the circadian rhythm of serum leptin was present in our mouse model and large variations in leptin concentrations, common in acute injections, were avoided (Ahima et al., 1996; Ahima et al., 1998). Furthermore, chronic injections can produce stress in rodents and are not feasible in the long-term, representing confounders that could have affected leptin’s trophic effect in earlier studies (Bouret et al., 2004b; Kamitakahara et al., 2018). Nevertheless, our results indicating that ARH projections can be recovered even in adult animals are consistent with the fact that exogenous leptin treatment is able to induce a robust weight loss and improvements in a variety of neuroendocrine and metabolic dysfunctions of Lep^ob/ob mice (Maffei et al., 1995; Montague et al., 1997; Farooqi et al., 2002; Bellefontaine et al., 2014).

Individual values were plotted in each figure and source data files have also been included.

1. 1. Ahima RS
   2. Prabakaran D
   3. Mantzoros C
   4. Qu D
   5. Lowell B
   6. Maratos-Flier E
   7. Flier JS

   (1996) Role of leptin in the neuroendocrine response to fasting

   Nature 382:250–252.

   https://doi.org/10.1038/382250a0

   • PubMed
   • Google Scholar
2. 1. Ahima RS
   2. Prabakaran D
   3. Flier JS

   (1998) Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. implications for energy homeostasis and neuroendocrine function

   Journal of Clinical Investigation 101:1020–1027.

   https://doi.org/10.1172/JCI1176

   • PubMed
   • Google Scholar
3. 1. Ahima RS
   2. Bjorbaek C
   3. Osei S
   4. Flier JS

   (1999) Regulation of neuronal and glial proteins by leptin: implications for brain development

   Endocrinology 140:2755–2762.

   https://doi.org/10.1210/endo.140.6.6774

   • PubMed
   • Google Scholar
4. 1. Attig L
   2. Solomon G
   3. Ferezou J
   4. Abdennebi-Najar L
   5. Taouis M
   6. Gertler A
   7. Djiane J

   (2008) Early postnatal leptin blockage leads to a long-term leptin resistance and susceptibility to diet-induced obesity in rats

   International Journal of Obesity 32:1153–1160.

   https://doi.org/10.1038/ijo.2008.39

   • Google Scholar
5. 1. Bates SH
   2. Stearns WH
   3. Dundon TA
   4. Schubert M
   5. Tso AW
   6. Wang Y
   7. Banks AS
   8. Lavery HJ
   9. Haq AK
   10. Maratos-Flier E
   11. Neel BG
   12. Schwartz MW
   13. Myers MG

   (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction

   Nature 421:856–859.

   https://doi.org/10.1038/nature01388

   • PubMed
   • Google Scholar
6. 1. Bellefontaine N
   2. Chachlaki K
   3. Parkash J
   4. Vanacker C
   5. Colledge W
   6. d'Anglemont de Tassigny X
   7. Garthwaite J
   8. Bouret SG
   9. Prevot V

   (2014) Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

   Journal of Clinical Investigation 124:2550–2559.

   https://doi.org/10.1172/JCI65928

   • PubMed
   • Google Scholar
7. 1. Bereiter DA
   2. Jeanrenaud B

   (1979) Altered neuroanatomical organization in the central nervous system of the genetically obese (ob/ob) mouse

   Brain Research 165:249–260.

   https://doi.org/10.1016/0006-8993(79)90557-2

   • PubMed
   • Google Scholar
8. 1. Berglund ED
   2. Vianna CR
   3. Donato J
   4. Kim MH
   5. Chuang JC
   6. Lee CE
   7. Lauzon DA
   8. Lin P
   9. Brule LJ
   10. Scott MM
   11. Coppari R
   12. Elmquist JK

   (2012) Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

   Journal of Clinical Investigation 122:1000–1009.

   https://doi.org/10.1172/JCI59816

   • PubMed
   • Google Scholar
9. 1. Bock T
   2. Pakkenberg B
   3. Buschard K

   (2003) Increased islet volume but unchanged islet number in ob/ob mice

   Diabetes 52:1716–1722.

   https://doi.org/10.2337/diabetes.52.7.1716

   • PubMed
   • Google Scholar
10. 1. Bouret SG
    2. Draper SJ
    3. Simerly RB

    (2004a) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice

    Journal of Neuroscience 24:2797–2805.

    https://doi.org/10.1523/JNEUROSCI.5369-03.2004

    • PubMed
    • Google Scholar
11. 1. Bouret SG
    2. Draper SJ
    3. Simerly RB

    (2004b) Trophic action of leptin on hypothalamic neurons that regulate feeding

    Science 304:108–110.

    https://doi.org/10.1126/science.1095004

    • PubMed
    • Google Scholar
12. 1. Bumaschny VF
    2. Yamashita M
    3. Casas-Cordero R
    4. Otero-Corchón V
    5. de Souza FS
    6. Rubinstein M
    7. Low MJ

    (2012) Obesity-programmed mice are rescued by early genetic intervention

    Journal of Clinical Investigation 122:4203–4212.

    https://doi.org/10.1172/JCI62543

    • PubMed
    • Google Scholar
13. 1. Caron E
    2. Sachot C
    3. Prevot V
    4. Bouret SG

    (2010) Distribution of leptin-sensitive cells in the postnatal and adult mouse brain

    The Journal of Comparative Neurology 518:459–476.

    https://doi.org/10.1002/cne.22219

    • PubMed
    • Google Scholar
14. 1. Chehab FF
    2. Lim ME
    3. Lu R

    (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin

    Nature Genetics 12:318–320.

    https://doi.org/10.1038/ng0396-318

    • PubMed
    • Google Scholar
15. 1. Chen H
    2. Simar D
    3. Morris MJ

    (2009) Hypothalamic neuroendocrine circuitry is programmed by maternal obesity: interaction with postnatal nutritional environment

    PLOS ONE 4:e6259.

    https://doi.org/10.1371/journal.pone.0006259

    • PubMed
    • Google Scholar
16. 1. Chhabra KH
    2. Adams JM
    3. Jones GL
    4. Yamashita M
    5. Schlapschy M
    6. Skerra A
    7. Rubinstein M
    8. Low MJ

    (2016) Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and pomc gene expression reverts extreme obesity

    Molecular Metabolism 5:869–881.

    https://doi.org/10.1016/j.molmet.2016.07.012

    • PubMed
    • Google Scholar
17. 1. Cunningham SA
    2. Kramer MR
    3. Narayan KM

    (2014) Incidence of childhood obesity in the united states

    New England Journal of Medicine 370:403–411.

    https://doi.org/10.1056/NEJMoa1309753

    • PubMed
    • Google Scholar
18. 1. Dodd GT
    2. Worth AA
    3. Nunn N
    4. Korpal AK
    5. Bechtold DA
    6. Allison MB
    7. Myers MG
    8. Statnick MA
    9. Luckman SM

    (2014) The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus

    Cell Metabolism 20:639–649.

    https://doi.org/10.1016/j.cmet.2014.07.022

    • PubMed
    • Google Scholar
19. 1. Donato J
    2. Cravo RM
    3. Frazão R
    4. Gautron L
    5. Scott MM
    6. Lachey J
    7. Castro IA
    8. Margatho LO
    9. Lee S
    10. Lee C
    11. Richardson JA
    12. Friedman J
    13. Chua S
    14. Coppari R
    15. Zigman JM
    16. Elmquist JK
    17. Elias CF

    (2011) Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

    Journal of Clinical Investigation 121:355–368.

    https://doi.org/10.1172/JCI45106

    • PubMed
    • Google Scholar
20. 1. Farooqi IS
    2. Matarese G
    3. Lord GM
    4. Keogh JM
    5. Lawrence E
    6. Agwu C
    7. Sanna V
    8. Jebb SA
    9. Perna F
    10. Fontana S
    11. Lechler RI
    12. DePaoli AM
    13. O'Rahilly S

    (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency

    Journal of Clinical Investigation 110:1093–1103.

    https://doi.org/10.1172/JCI0215693

    • PubMed
    • Google Scholar
21. 1. Haberland M
    2. Montgomery RL
    3. Olson EN

    (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy

    Nature Reviews Genetics 10:32–42.

    https://doi.org/10.1038/nrg2485

    • PubMed
    • Google Scholar
22. 1. Halaas JL
    2. Gajiwala KS
    3. Maffei M
    4. Cohen SL
    5. Chait BT
    6. Rabinowitz D
    7. Lallone RL
    8. Burley SK
    9. Friedman JM

    (1995) Weight-reducing effects of the plasma protein encoded by the obese gene

    Science 269:543–546.

    https://doi.org/10.1126/science.7624777

    • PubMed
    • Google Scholar
23. 1. Hommel JD
    2. Trinko R
    3. Sears RM
    4. Georgescu D
    5. Liu ZW
    6. Gao XB
    7. Thurmon JJ
    8. Marinelli M
    9. DiLeone RJ

    (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding

    Neuron 51:801–810.

    https://doi.org/10.1016/j.neuron.2006.08.023

    • PubMed
    • Google Scholar
24. 1. Ioffe E
    2. Moon B
    3. Connolly E
    4. Friedman JM

    (1998) Abnormal regulation of the leptin gene in the pathogenesis of obesity

    PNAS 95:11852–11857.

    https://doi.org/10.1073/pnas.95.20.11852

    • PubMed
    • Google Scholar
25. 1. Kabra DG
    2. Pfuhlmann K
    3. García-Cáceres C
    4. Schriever SC
    5. Casquero García V
    6. Kebede AF
    7. Fuente-Martin E
    8. Trivedi C
    9. Heppner K
    10. Uhlenhaut NH
    11. Legutko B
    12. Kabra UD
    13. Gao Y
    14. Yi CX
    15. Quarta C
    16. Clemmensen C
    17. Finan B
    18. Müller TD
    19. Meyer CW
    20. Paez-Pereda M
    21. Stemmer K
    22. Woods SC
    23. Perez-Tilve D
    24. Schneider R
    25. Olson EN
    26. Tschöp MH
    27. Pfluger PT

    (2016) Hypothalamic leptin action is mediated by histone deacetylase 5

    Nature Communications 7:10782.

    https://doi.org/10.1038/ncomms10782

    • PubMed
    • Google Scholar
26. 1. Kamitakahara A
    2. Bouyer K
    3. Wang CH
    4. Simerly R

    (2018) A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus

    Journal of Comparative Neurology 526:133–145.

    https://doi.org/10.1002/cne.24327

    • PubMed
    • Google Scholar
27. 1. Kohno D
    2. Lee S
    3. Harper MJ
    4. Kim KW
    5. Sone H
    6. Sasaki T
    7. Kitamura T
    8. Fan G
    9. Elmquist JK

    (2014) Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis

    Journal of Neuroscience 34:15288–15296.

    https://doi.org/10.1523/JNEUROSCI.1316-14.2014

    • PubMed
    • Google Scholar
28. 1. Ladyman SR
    2. Grattan DR

    (2005) Suppression of leptin receptor messenger ribonucleic acid and leptin responsiveness in the ventromedial nucleus of the hypothalamus during pregnancy in the rat

    Endocrinology 146:3868–3874.

    https://doi.org/10.1210/en.2005-0194

    • PubMed
    • Google Scholar
29. 1. Leibel RL
    2. Rosenbaum M
    3. Hirsch J

    (1995) Changes in energy expenditure resulting from altered body weight

    New England Journal of Medicine 332:621–628.

    https://doi.org/10.1056/NEJM199503093321001

    • PubMed
    • Google Scholar
30. 1. Licinio J
    2. Caglayan S
    3. Ozata M
    4. Yildiz BO
    5. de Miranda PB
    6. O'Kirwan F
    7. Whitby R
    8. Liang L
    9. Cohen P
    10. Bhasin S
    11. Krauss RM
    12. Veldhuis JD
    13. Wagner AJ
    14. DePaoli AM
    15. McCann SM
    16. Wong ML

    (2004) Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

    PNAS 101:4531–4536.

    https://doi.org/10.1073/pnas.0308767101

    • PubMed
    • Google Scholar
31. 1. Lillycrop KA
    2. Burdge GC

    (2011) Epigenetic changes in early life and future risk of obesity

    International Journal of Obesity 35:72–83.

    https://doi.org/10.1038/ijo.2010.122

    • Google Scholar
32. 1. Liu J
    2. Perez SM
    3. Zhang W
    4. Lodge DJ
    5. Lu XY

    (2011) Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala

    Molecular Psychiatry 16:1024–1038.

    https://doi.org/10.1038/mp.2011.36

    • PubMed
    • Google Scholar
33. 1. Maffei M
    2. Halaas J
    3. Ravussin E
    4. Pratley RE
    5. Lee GH
    6. Zhang Y
    7. Fei H
    8. Kim S
    9. Lallone R
    10. Ranganathan S

    (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

    Nature Medicine 1:1155–1161.

    https://doi.org/10.1038/nm1195-1155

    • PubMed
    • Google Scholar
34. 1. Martin RL
    2. Perez E
    3. He YJ
    4. Dawson R
    5. Millard WJ

    (2000) Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation

    Metabolism 49:1479–1484.

    https://doi.org/10.1053/meta.2000.17695

    • PubMed
    • Google Scholar
35. 1. Messager S
    2. Chatzidaki EE
    3. Ma D
    4. Hendrick AG
    5. Zahn D
    6. Dixon J
    7. Thresher RR
    8. Malinge I
    9. Lomet D
    10. Carlton MB
    11. Colledge WH
    12. Caraty A
    13. Aparicio SA

    (2005) Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54

    PNAS 102:1761–1766.

    https://doi.org/10.1073/pnas.0409330102

    • PubMed
    • Google Scholar
36. 1. Mistry AM
    2. Swick A
    3. Romsos DR

    (1999) Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice

    American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277:R742–R747.

    https://doi.org/10.1152/ajpregu.1999.277.3.R742

    • Google Scholar
37. 1. Montague CT
    2. Farooqi IS
    3. Whitehead JP
    4. Soos MA
    5. Rau H
    6. Wareham NJ
    7. Sewter CP
    8. Digby JE
    9. Mohammed SN
    10. Hurst JA
    11. Cheetham CH
    12. Earley AR
    13. Barnett AH
    14. Prins JB
    15. O'Rahilly S

    (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans

    Nature 387:903–908.

    https://doi.org/10.1038/43185

    • PubMed
    • Google Scholar
38. 1. Mounzih K
    2. Lu R
    3. Chehab FF

    (1997) Leptin treatment rescues the sterility of genetically obese ob/ob males

    Endocrinology 138:1190–1193.

    https://doi.org/10.1210/endo.138.3.5024

    • PubMed
    • Google Scholar
39. 1. Paz-Filho GJ
    2. Babikian T
    3. Asarnow R
    4. Delibasi T
    5. Esposito K
    6. Erol HK
    7. Wong ML
    8. Licinio J

    (2008) Leptin replacement improves cognitive development

    PLOS ONE 3:e3098.

    https://doi.org/10.1371/journal.pone.0003098

    • PubMed
    • Google Scholar
40. 1. Pelleymounter MA
    2. Cullen MJ
    3. Baker MB
    4. Hecht R
    5. Winters D
    6. Boone T
    7. Collins F

    (1995) Effects of the obese gene product on body weight regulation in ob/ob mice

    Science 269:540–543.

    https://doi.org/10.1126/science.7624776

    • PubMed
    • Google Scholar
41. 1. Pinto S
    2. Roseberry AG
    3. Liu H
    4. Diano S
    5. Shanabrough M
    6. Cai X
    7. Friedman JM
    8. Horvath TL

    (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin

    Science 304:110–115.

    https://doi.org/10.1126/science.1089459

    • PubMed
    • Google Scholar
42. 1. Polkowska J
    2. Wójcik-Gładysz A
    3. Wańkowska M

    (2006) The effect of intracerebroventricular infusions of leptin on the immunoreactivity of neuropeptide Y and gonadotrophin releasing hormone neurons in the hypothalamus of prepubertal sheep in conditions of short fasting

    Journal of Chemical Neuroanatomy 32:65–73.

    https://doi.org/10.1016/j.jchemneu.2006.05.001

    • PubMed
    • Google Scholar
43. 1. Ralevski A
    2. Horvath TL

    (2015) Developmental programming of hypothalamic neuroendocrine systems

    Frontiers in Neuroendocrinology 39:52–58.

    https://doi.org/10.1016/j.yfrne.2015.09.002

    • PubMed
    • Google Scholar
44. 1. Ramos-Lobo AM
    2. Donato J

    (2017) The role of leptin in health and disease

    Temperature 4:258–291.

    https://doi.org/10.1080/23328940.2017.1327003

    • Google Scholar
45. 1. Samuelsson AM
    2. Matthews PA
    3. Argenton M
    4. Christie MR
    5. McConnell JM
    6. Jansen EH
    7. Piersma AH
    8. Ozanne SE
    9. Twinn DF
    10. Remacle C
    11. Rowlerson A
    12. Poston L
    13. Taylor PD

    (2008) Diet-induced obesity in female mice leads to offspring Hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming

    Hypertension 51:383–392.

    https://doi.org/10.1161/HYPERTENSIONAHA.107.101477

    • PubMed
    • Google Scholar
46. 1. Sena A
    2. Sarliève LL
    3. Rebel G

    (1985) Brain myelin of genetically obese mice

    Journal of the Neurological Sciences 68:233–244.

    https://doi.org/10.1016/0022-510X(85)90104-2

    • PubMed
    • Google Scholar
47. 1. van der Kroon PH
    2. Speijers GJ

    (1979) Brain deviations in adult obese-hyperglycemic mice (ob/ob)

    Metabolism 28:1–3.

    https://doi.org/10.1016/0026-0495(79)90160-4

    • PubMed
    • Google Scholar
48. 1. Vickers MH
    2. Gluckman PD
    3. Coveny AH
    4. Hofman PL
    5. Cutfield WS
    6. Gertler A
    7. Breier BH
    8. Harris M

    (2005) Neonatal leptin treatment reverses developmental programming

    Endocrinology 146:4211–4216.

    https://doi.org/10.1210/en.2005-0581

    • PubMed
    • Google Scholar
49. 1. Vogt MC
    2. Paeger L
    3. Hess S
    4. Steculorum SM
    5. Awazawa M
    6. Hampel B
    7. Neupert S
    8. Nicholls HT
    9. Mauer J
    10. Hausen AC
    11. Predel R
    12. Kloppenburg P
    13. Horvath TL
    14. Brüning JC

    (2014) Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding

    Cell 156:495–509.

    https://doi.org/10.1016/j.cell.2014.01.008

    • PubMed
    • Google Scholar
50. 1. Zhai L
    2. Zhao J
    3. Zhu Y
    4. Liu Q
    5. Niu W
    6. Liu C
    7. Wang Y

    (2018) Downregulation of leptin receptor and kisspeptin/GPR54 in the murine hypothalamus contributes to male hypogonadism caused by high-fat diet-induced obesity

    Endocrine 62:195–206.

    https://doi.org/10.1007/s12020-018-1646-9

    • PubMed
    • Google Scholar

Author details

1. Angela M Ramos-Lobo

   Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

   Contribution

   Data curation, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

2. Pryscila DS Teixeira

   Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

3. Isadora C Furigo

   Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

4. Helen M Melo

   Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

   Contribution

   Formal analysis, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

5. Natalia de M Lyra e Silva

   1. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
   2. Centre for Neuroscience Studies, Department of Psychiatry, Queen's University, Kingston, Canada

   Contribution

   Formal analysis, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

6. Fernanda G De Felice

   Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

   Contribution

   Formal analysis, Supervision, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

7. Jose Donato Jr

   Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Writing—original draft, Project administration

   For correspondence

   jdonato@icb.usp.br

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4166-7608

• 3,118

  views

• 422

  downloads

• 36

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.