Alessio Molfino*
Giovanni Imbimbo- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
Editorial on the Research Topic
Appetite Control in Obesity
Obesity represents a worldwide major health problem with a prevalence growing exponentially in the last decades (1). This phenomenon increases the major risk factors for developing several chronic conditions such as diabetes, cardiovascular disease, cancer and chronic kidney disease (1, 2). Importantly, obesity and overweight in the adult population have been associated with a strong reduction in life expectancy and with increased early mortality (3). In adulthood, obesity was found to be a powerful predictor of mortality also at older ages (4). In parallel, obesity determines an important economic burden on nations and on single individuals (5) with a global economic impact that was estimated in 2030 to be around US $2.0 trillion or ~3% of the global gross domestic product (6, 7).
From a pathophysiological point of view, the obesity phenotype is the consequence of a long-term altered energy balance with an increased energy intake and decreased calorie expenditure (8, 9).
The mechanisms are multifactorial, including interaction among genetic, epigenetic, physiological and psychological aspects with the environment (8). A crucial factor is represented by the modulation of energy homeostasis mediated by the central nervous system (8), and appetite is mainly regulated by three systems: (i) the Agouti-related protein (AGRP) neurons that are located in the hypothalamic arcuate nucleus (ARC) and stimulating food intake; (ii) neurons in lateral hypothalamus that are involved in positive feedback for increasing food assumption; (iii) neurons in the parabrachial nucleus that are potent suppressors of food intake. This system physiologically interacts with internal and external stimuli regulating the energy balance (8, 10, 11).
In this light, the understanding of the mechanisms underlying appetite regulation/dysregulation is of great interest in order to develop new therapeutic strategies to counteract obesity and the associated negative consequences.
Altered appetite represents the substrate for different diseases that may lead to two opposite phenotypes, i.e., obesity and malnutrition. Except for rare genetic conditions, such as MC4R deficiency, hyperphagia in obese patients is often driven mainly by different environmental factors, including dietary patterns (in particular, western diets), abundance of high palatable food and to psychological aspects (e.g., anxiety, lack of sleep) influencing the daily calorie intakes (9). However, excluding the rare monogenic syndromes, in obesity genome wide association studies (GWAS) identified different loci associated with an obese phenotype which may represent a genetic predisposition (12, 13). In particular, a recent study found 112 new loci that were not previously identified among the ones associated with high body mass index (BMI) in the Japanese population (12). Interestingly, this study showed a genetic correlation between lymphocyte count and BMI, providing insights in body weight regulation and lymphocytes to be furtherly investigated (12).
By GWAS studies, glucosamine-6-phosphate deaminase (GNPDA2) was associated with obesity (14) and in a recent article appeared in the present Research Topic of Frontiers in Nutrition, Gutierrez-Aguilar et al. observed in an animal model that, although GNPDA2 seemed not involved in appetite regulation at central level, it may play a role in glucose homeostasis.
Also, the fat mass and obesity-related (FTO) variants were extensively investigated due to their association(s) with increased BMI. In fact, the FTO gene variants were considered important determinants of impaired energy balance and, in turn, obesity (15).
More recently, several studies focused on the epigenetic mechanisms as contributor for the development of different metabolic derangements including obesity (16). Interestingly, the evaluation of epigenetic alterations in BDNF promoter in children showed a preliminary association with appetite modulation (17). In this light, the study of the epigenetics mechanisms regarding appetite regulation may explain the interaction between environment and body weight homeostasis. Importantly, the understanding of human epigenome and its interaction with the pathogenesis of obesity may provide advanced and personalized therapeutic strategies.
Interestingly, different molecules regulating energy homeostasis were described to be able to modulate appetite in different settings. For instance, the growth differentiation factor 15 (GDF15)—an inflammatory cytokine—was initially investigated for its role in pathophysiology of cancer anorexia (18, 19). In particular, a recent study showed that GDF15 determined reduced appetite and, in turn low food intake binding in the area postrema and nucleus of the solitary tract the GDNF family receptor α-like (GFRAL) and its co-receptor Ret proto-oncogene (RET) (20). In this light, the GDF15-GFRAL axis was considered for obesity therapy showing promising results in animal studies (21). Moreover, GDF15 may have anti-obese effects determining fat loss inducing thermogenesis (22).
Also, the Lipocalin-2 (LCN2) is a novel bone-derived mediator able to suppress food intake by the interaction with the melanocortin receptor 4 (MC4R) in the hypothalamus (23). The role of LCN2 was also investigated in the setting of obesity (24) showing that LCN2 may act by the modulation of appetite and by inducing β-cell proliferation, serving as compensatory signal (25). Elucidating the role of bone in appetite control in obesity may clarify the role of LCN2 in this setting.
Interestingly, Maric et al. analyzed using experimental models (mice and rats) potential differences of diet-induced obesity according to sex and found that male and female animals responded in a different way to high fat diet by different metabolic compensatory pathways and this divergence was seen also between mice and rats.
In addition, the role of some vitamins (vitamin E and K2) have been investigated in metabolic syndrome and in fat metabolism by Zhang et al. and Qu et al.
Nowadays, different drugs were approved by FDA for obesity treatments (24), including phentermine, lorcaserin, naltrexone and liraglutide acting on CNS reducing appetite, and the orlistat decreasing fat absorption (24). Although these drugs showed capability to reduce body weight in clinical trials, the efficacy of these therapies is still considered limited. On the other side, several drugs, in particular antipsychotics, may dramatically affect appetite and understating their effects on energy homeostasis have been well analyzed by Mukherjee et al., focusing on the receptor binding profile of these drugs.
For all these considerations, the interest of appetite regulation in obesity analyzed in the present Research Topic may highlight new pathways involved in obesity and their role for the development of novel personalized anti-obesity treatments.
Author Contributions
AM and GI wrote the article. Both authors contributed to manuscript revision, read, and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
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References
1. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. (2017) 377:13–27. doi: 10.1056/NEJMoa1614362
2. Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. (2009) 373:1083–96. doi: 10.1016/S0140-6736(09)60318-4
3. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. (2003) 289:187–93. doi: 10.1001/jama.289.2.187
4. Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L, et al. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. (2003) 138:24–32. doi: 10.7326/0003-4819-138-1-200301070-00008
5. OECD. The Heavy Burden of Obesity: The Economics of Prevention, OECD Health Policy Studies. Paris: OECD Publishing (2019).
6. Dobbs R, Sawers C, Thompson F, Manyika J, Woetzel JR, Child P, et al. Overcoming Obesity: An Initial Economic Analysis. Jakarta: McKiney Global Institute (2014)
7. Tremmel M, Gerdtham UG, Nilsson PM, Saha S. Economic burden of obesity: a systematic literature review. Int J Environ Res Public Health. (2017) 14:435. doi: 10.3390/ijerph14040435
8. Sternson SM, Eiselt AK. Three pillars for the neural control of appetite. Annu Rev Physiol. (2017) 79:401–23. doi: 10.1146/annurev-physiol-021115-104948
9. Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. (2019) 15:288–98. doi: 10.1038/s41574-019-0176-8
10. Augustine V, Lee S, Oka Y. Neural control and modulation of thirst, sodium appetite, and hunger. Cell. (2020) 180:25–32. doi: 10.1016/j.cell.2019.11.040
11. MacLean PS, Blundell JE, Mennella JA, Batterham RL. Biological control of appetite: a daunting complexity. Obesity. (2017) 25 (Suppl 1):S8–16. doi: 10.1002/oby.21771
12. Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M. Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. Nat Genet. (2017) 49:1458–67. doi: 10.1038/ng.3951
13. Rohde K, Keller M, la Cour Poulsen L, Blüher M, Kovacs P, Böttcher Y. Genetics and epigenetics in obesity. Metab Clin Exp. (2019) 92:37–50. doi: 10.1016/j.metabol.2018.10.007
14. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. (2010) 42:937–48. doi: 10.1038/ng.686
15. Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, et al. FTO obesity variant circuitry and adipocyte browning in humans. N Engl J Med. (2015) 373:895–907. doi: 10.1056/NEJMoa1502214
16. Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. (2019) 29:1028–44. doi: 10.1016/j.cmet.2019.03.009
17. Gardner KR, Sapienza C, Fisher JO. Genetic and epigenetic associations to obesity-related appetite phenotypes among African-American children. Pediatr Obes. (2015) 10:476–82. doi: 10.1111/ijpo.12010
18. Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med. (2007) 13:1333–40. doi: 10.1038/nm1677
19. Molfino A, Amabile MI, Imbimbo G, Rizzo V, Pediconi F, Catalano C, et al. Association between growth differentiation factor-15 (GDF-15) serum levels, anorexia and low muscle mass among cancer patients. Cancers. (2020) 13:99. doi: 10.3390/cancers13010099
20. Yang L, Chang CC, Sun Z, Madsen D, Zhu H, Padkjær SB, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. (2017) 23:1158–66. doi: 10.1038/nm.4394
21. Tsai V, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. (2018) 28:353–68. doi: 10.1016/j.cmet.2018.07.018
22. Oka M, Kobayashi N, Matsumura K, Nishio M, Nakano K, Okamura T, et al. New role for growth/differentiation factor 15 in the survival of transplanted brown adipose tissues in cooperation with interleukin-6. Cells. (2020) 9:1365. doi: 10.3390/cells9061365
23. Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z, et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. (2017) 543:385–90. doi: 10.1038/nature21697
24. Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinol. (2018) 14:12–24. doi: 10.1038/nrendo.2017.122
Keywords: obesity, overweight, appetite, energy homeostasis, therapy
Citation: Molfino A and Imbimbo G (2022) Editorial: Appetite Control in Obesity. Front. Nutr. 9:959627. doi: 10.3389/fnut.2022.959627
Received: 01 June 2022; Accepted: 16 June 2022;
Published: 28 June 2022.
Edited and reviewed by: Ellen E. Blaak, Maastricht University, Netherlands
Copyright © 2022 Molfino and Imbimbo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alessio Molfino, alessio.molfino@uniroma1.it