Genetic variability in the leptin-melanocortin pathway and its role in weight loss

Abstract

Obesity is a multifactorial disease characterized by an excessive and abnormal accumulation of body fat that results from both genetic and environmental factors. In this review, we revisited the literature on the variability of obesity-associated genes and their impact on the effectiveness of obesity treatment interventions. Individuals harboring variants of these genes were found to have either better or worse outcomes after weight loss therapies. The majority of the genetic variants were identified in genes that play a role in the leptin-melanocortin pathway (LEPR, NPY, POMC, MC4R, GHRL, GHSR, GLP-1R, BDNF), which regulates food intake and energy expenditure. Both these processes are key elements for energy homeostasis, therefore relevant for the success/failure of weight loss strategies. Some genetic alterations were found to modulate the outcomes of different weight loss interventions, while others were only linked to the effectiveness of bariatric surgery, according to the studies here included and available. Herein, we revisited the most relevant molecular data, with a primarily focus on human studies, concerning how the genetic background influences the outcomes of weight loss interventions. Our aim is to gather relevant information on the genetic data related to weight loss strategies that can be compelling to guide clinical decisions, setting realistic expectations, and ultimately improving the long-term health conditions of individuals with obesity.

1. Obesity

Obesity is a complex disease characterized by a disruption of the energy homeostasis [1]. Obesity is defined by the World Health Organization (WHO) as “an abnormal and excessive accumulation of fat that impairs health” [2]. Adipose tissue malfunction is a result of the interaction between genetic and environmental factors [3], which can lead to the onset and progression of obesity-associated complications [4]. Obesity is linked to increased risk for over 200 other medical conditions, including cardiovascular diseases [5], hypertension [6], respiratory diseases [7], type 2 diabetes (T2D) [8], dyslipidemia [9], liver diseases [10], cancer [11], and infertility [12], as well as heightened rates of premature mortality [13,14].

Being a multifactorial disease, several factors contribute to its manifestations, including genetic predisposition, lifestyle, environmental conditions, hormone dynamics, medications, endocrine disruptors, among other metabolic-related factors [15]. Still, from an epidemiological point of view, there is no doubt that the adoption of a sedentary lifestyle and excessive-calorie intake, characteristics of modern societies, have significantly imbalanced energy homeostasis and contributed to the global rise of obesity prevalence [16].

2. Obesity treatment interventions

Although excess body fat is a well-established root cause of many obesity-related health conditions, there is also evidence that even modest weight loss (WL) can lead to significant health benefits. It has been demonstrated that a 5–10% WL can contribute to clinically relevant improvements in several obesity-associated complications, including lowering blood glucose, blood pressure, and lipids, as well as reducing medication needs and, most importantly, improving quality of life [17]. However, the magnitude of WL required to yield health benefits varies: reductions in blood glucose and triglycerides levels have been observed with as little as a 3% WL, while blood pressure lowering typically begins at around 5% WL. In contrast, conditions such as obstructive sleep apnea and steatohepatitis generally require more than 10% WL before ameliorations can be witnessed [18].

Importantly, regardless of the magnitude of WL achieved, which can be attained by diet and exercise, alone or in combination with pharmacotherapy or bariatric surgery as appropriate, it has a tangible impact on the health of individuals [19].

2.1. Lifestyle-based interventions

Body weight results from an equilibrium between energy intake and expenditure [20]. Weight gain and the development of excess body weight result from a positive energy balance, which requires a higher calorie intake and lower energy expenditure due to reduced physical activity. The maladjustment between the high-calorie dietary intake and the low energy demands of the modern lifestyle is the major contributor to the rising prevalence of obesity [20,21]. Therefore, to induce WL, a negative energy balance is required. This can be achieved by dietary interventions involving caloric restriction alone or combined with physical activity to increase energy expenditure, which are used to promote WL and reduce adiposity in individuals with overweight or obesity [22]. These lifestyle interventions are expected to achieve a 3–5% reduction in body weight and a clinically relevant improvement of obesity-associated complications [23]. Nonetheless, the greatest challenge lies in body weight maintenance after WL is attained through lifestyle interventions that require a long-term commitment to a diet tailored to meet the individual's nutritional needs and behavioral modifications, including adequate levels of physical activity, to be able to counteract the physiological mechanisms triggered to restore the initial weight [24].

2.2. Pharmacotherapy

Pharmacotherapy is indicated for the treatment of people with obesity or overweight in the presence of obesity-associated complications whenever lifestyle interventions have proved to fail to achieve adequate WL [25]. Over the past decade, substantial progress has been made in the development of new obesity management drugs that utilize analogues of hormones involved in signaling the body's energy status to the brain, liver, and adipose tissue. These include glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and a dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonist (GILP-1R/GIPR), while several others are on the horizon [26]. This new class of drugs has been demonstrated to be able to induce over 5%–20% WL and improve obesity-associated complications [27]. The GLP-1RAs act at the central nervous system to increase satiety and reduce hunger, ultimately contributing to decreased food intake and WL. Moreover, GLP-1RAs act at peripheral organs to slow gastric emptying and improve insulin sensitivity [28]. GIPR agonism may enhance the central and peripheral actions of GLP-1RA and facilitate the healthy storage of excess lipids in the adipose tissue, thereby reducing ectopic fat accumulation in other organs, such as the liver [29].

The GLP-1RAs class accounts for several drugs already marketed and licensed for obesity and T2D treatment, such as liraglutide, semaglutide, and tirzepatide. The firs-in-class to be licensed for obesity treatment was liraglutide, a short-acting GLP-1RA with 97% homology to native GLP-1 [30]. Liraglutide has been demonstrated to be effective in achieving a body weight reduction of 5–10% and maintaining WL [31]. Semaglutide, a long-acting GLP-1RA that shares 94% homology with native GLP-1, demonstrated to achieve greater weight reductions, with an average of approximately 15% WL, with some individuals losing even 20% of their initial body weight [32]. Tirzepatide is the first-in-class dual agonist, which targets both the GLP-1 and GIP receptors [29,33] and promotes WL in a dose-dependent manner up to approximately 21% at the 15 mg dose [34]. These drugs are currently used worldwide as first-line pharmacotherapy for WL in individuals with overweight or obesity, other than syndromic or monogenetic obesity.

Setmelanotide is a cyclic peptide that belongs to a different drug class and acts predominantly as a melanocortin-4 receptor (MC4R) agonist, a key regulator of energy balance, appetite, and body weight. Setmelanotide is approved for the treatment of obesity caused by rare syndromic and monogenetic disorders affecting the melanocortin anorexigenic pathway. These include biallelic mutations in genes involved such as the proopiomelanocortin (POMC), proprotein subtilisin/kexin type 1 (PCSK1) and the leptin receptor (LEPR), as well as individuals with Bardet-Biedl syndrome [35,36]. Setmelanotide binds to and activates several melanocortin receptors involved in the suppression of appetite and thereby promotes WL [37,38]. Previous data revealed a weight reduction of 10% in 80% of the individuals with POMC deficiency and 46% of the individuals with LEPR deficiency [35].

3. Bariatric surgery

Bariatric surgery is the most effective treatment for individuals with a Body Mass Index (BMI) equal or greater than 35 kg/m² or 30 kg/m² in the presence of obesity-associated complications, in whom the abovementioned non-surgical interventions obtained a suboptimal clinical response [39]. Bariatric surgery is considered a safe intervention for managing obesity and its complications, since the benefits were demonstrated by large to outweigh the putative surgical risks [40]. The bariatric procedures recognized by the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) are sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion (BPD) with or without duodenal switch (DS), single-anastomosis duodenal-ileal bypass (SADI) with or without DS (SADI-S) and laparoscopic gastric banding (LGB) [41,42]. SG consists of the reduction of the gastric volume by 75% through the construction of a vertical calibrated gastric sleeve [43]. SG reduces stomach volume and limits food intake capacity [44], leading to a substantial WL and improvement of several obesity-associated complications [45]. RYGB consists of the creation of a small gastric pouch on the lesser gastric curvature, which is then anastomosed to the distal small intestine, bypassing the proximal gut [46]. This technique is linked to significant WL, improvement in obesity-associated complications, and most particularly T2D, as well as improved quality of life and reduced rates of premature mortality [47]. BPD or BPD/DS consists of a vertically calibrated gastrectomy aiding an entero-enteric anastomosis with RY reconstruction in case of DS. BPD and BPD/DS are the most complex bariatric surgery procedures, but also result in the greatest WL and improvement of obesity-associated complications, such as T2D [48]. LGB consists in the placement of a synthetic adjustable band below the gastroesophageal junction with the goal to create a gastric pouch. This procedure is linked to significant WL outcomes and the improvement of obesity-associated complications [46].

The WL outcomes following bariatric surgery can vary depending on patient characteristics and type of surgical procedure, though the vast majority of patients typically reach their maximum WL within one to two years after surgery [49,50]. An optimal surgical outcome is defined as achieving at least 20% WL and/or significant improvement of obesity-associated complications, such as T2D [51]. Although highly effective, some individuals present suboptimal outcomes after bariatric surgery, which can be due to factors such as age, obesity-associated complications, gender, BMI, and the genetic background [52]. These suboptimal outcomes can be defined as insufficient WL or failure to remit or relapse of obesity-associated complications. These are classified as primary suboptimal response, defined as failure to achieve adequate WL after the procedure or inadequate improvement of an obesity-associated complication, such as persistent T2D, and as secondary suboptimal response, characterized by a significant weight regain following optimal WL after the procedure or relapse of an obesity-related complication after initial remission, like T2D [42,53]. Pharmacotherapy or revisional bariatric surgery may be recommended for individuals in case of suboptimal WL or persistence of obesity-associated conditions, weight regain, or relapse of obesity-associated complications [54,55].

4. Genetic variants associated with obesity and their influence on weight loss outcomes

Genetic factors play a significant role in the onset and development of obesity [56]. Obesity can have a monogenic or a polygenic origin. Monogenic obesity results from pathogenic variation in a single gene, such as LEPR, POMC, or MC4R [57,58]. Polygenic obesity results from the interaction of multiple genes and variants that participate in the regulation of body weight. Several genes identified as causal of monogenic obesity have also been implicated in polygenic obesity (summarized in Table 1). In these genes, rare variants with high impact result in monogenic forms, whereas common low-penetrant variants modulate the polygenic forms of the disease [56]. Moreover, genetic variants may influence diseases differently depending on whether they are monoallelic mutations, in which only one of the alleles carries the variant (heterozygous), or are biallelic mutations, in which both alleles carry the variant (homozygous) [59]. Both monoallelic mutations, for example due to MC4R variants, as well as biallelic mutations, such as in leptin (LEP), LEPR and PCSK1, have been associated with severe early-onset obesity, as well as the development of the disease [60,61]. Genetic variants have a broad spectrum in their contribution not only to the onset and development of obesity, but also to the variability observed on the outcomes of WL interventions. In the following sections, some of the most relevant molecular mechanisms and pathways associated to WL interventions are examined in terms of their influence in metabolic regulation and energetic dynamics, focusing predominantly on human studies, except for one mouse model included (summarized in Supplementary Table 1).

Table 1.

Summary of genetic variants found to be associated with obesity; positive association whenever a gene variant linked to a greater likelihood for obesity or negative when the opposite was observed.

Gene	Variants linked to obesity
	Negative association	Positive association
FTO		rs9939609 (A) [[141], [142], [143], [144]]
		rs9930506 (G) [[145], [146], [147]]
LEPR		rs1137101 (G) [148,149]
NPY		rs16147 (TT) [105]
POMC		rs1042571 [108,150,151]
MC4R		rs17782313 (C) [112,152,153]
	rs52820871 [116]
GHRL		rs696217 (T) [154,155]
GLP-1R		rs6923761 (GG) [125,156]; (AA) [124]
BDNF	rs6265 (A) [131,132]	rs6265 (A) [157,158]
UCP2		rs660339 (CT/TT) [135,138,159]
	rs659366 (A) [[160], [161], [162]]	rs659366 (AA) [138]

4.1. Fat mass and obesity associated gene (FTO)

The fat mass and obesity associated (FTO) gene was the first obesity-susceptibility locus identified by genome-wide association studies (GWAS) [62]. A cluster of polymorphic variants within the first intron has been linked to obesity [63]. FTO has been associated with BMI, fat mass, and body weight [64], as well as with the regulation of food intake behavior and energy expenditure [65]. The protein encoded by FTO acts as a demethylase enzyme with a role in posttranscriptional regulation of transcripts involved in adipogenesis. FTO levels have been found to inversely correlate with the N6-methyladenosine (m6A) modification during adipogenesis, suggesting a role in gene regulation, particularly in the alternative splicing of mRNA [66,67]. The m6A modification participates in crucial physiological processes, such as DNA repair, and may modify the mRNA structure to modulate its stability, processing and translation. The methylated m6A modification intervenes in biological processes of cancer cells, like proliferation and metastasis [68].

One of the most studied variants associated with obesity is a T > A nucleotide replacement at intron 1 of the FTO gene. According to the Single Nucleotide Polymorphism Database (dbSNP, NCBI), the unique identifier for a variant is known as Reference SNP (rs or RefSNP) number. For the above mentioned nucleotide replacement at the FTO gene the identifier is rs9939609. Carriers of the A allele, when submitted to a lifestyle and/or diet intervention, have shown greater improvements in obesity-related blood parameters [69] and WL [70], despite women exhibiting a smaller reduction in abdominal circumference in response to a hypocaloric diet [71]. Yet, individuals with the A allele submitted to RYGB, representing 71.2% of those who underwent the procedure, were shown to be more likely to experience suboptimal WL response and weight regain post-RYGB, when compared to those with the TT genotype [72]. After BPD, the TT genotype also depicted greater WL in the first three months, as compared to the AT + AA genotypes, although at nine and twelve months after the surgery, there were no longer WL differences [73].

Other variants linked to FTO were also identified as being associated with the WL outcomes of obesity treatment interventions, such as the intronic A > G replacement (rs9930506). Young males with overweight or obesity who carried the A allele experienced a significant reduction in BMI following intensive lifestyle interventions as compared to those who carried the GG genotype [74]. The literature about the impact of this variant on the outcomes of bariatric surgery is less consistent. As an example, a study by Perez-Luque and collaborators found that individuals with the AG and GG genotypes exhibited less WL years after RYGB when compared to homozygous AA [75]. In contrast, Figueroa-Vega et al. showed that carriers of the AG or GG genotype exhibited a greater WL six months after SG than those with the AA genotype [76].

4.2. Genes involved in the leptin-melanocortin pathway

The melanocortin pathway is a complex neuroendocrine system that regulates energy homeostasis. This system encompasses the interaction between the central nervous system (CNS) and a multitude of hormones produced in the brain, gut, and adipose tissue, among many others [77]. These hormones act in the brainstem and hypothalamus, where the arcuate nucleus (ARC) lies, which is the center of hunger and satiety control. There are two types of neurons in the ARC, the orexigenic neurons, which express the neuropeptide Y (NPY) and the agouti-related protein (AgRP), responsible for appetite stimulation, and the anorexigenic neurons, which express POMC, that suppresses appetite [78]. The NPY gene is located in the central and peripheral nervous system, with important roles in cardiovascular, metabolic and immune processes [79]. The POMC gene is also highly expressed in the pituitary and is involved in several physiological processes, including the regulation of body weight [80].

The leptin-melanocortin pathway (Figure 1) is crucial for energy balance regulation by modulating appetite and energy expenditure [81]. Leptin is one of the main anorexigenic hormones and is released by adipocytes into circulation in proportion to fat mass. Leptin levels also vary according to the feeding patterns and nutritional state, with an increase after food intake [82]. Leptin acts through its receptor, LEPR, which is located at the membrane of the neurons in the ARC. The stimulated POMC-expressing neurons produce POMC, which is cleaved by PCSK1 to yield α-melanocyte-stimulating hormone (α-MSH), crucial for appetite inhibition. Then, α-MSH released from the POMC-expressing neurons’ axon terminals activates MC4R at the paraventricular nucleus (PVN) neurons, resulting in a satiety signal and consequently suppressing food intake [56,83]. Thus, MC4R intervenes in the regulation of food intake and body weight [84] by participating in the equilibrium between α-MSH and AgRP, an endogenous MC4R antagonist [85]. On the other hand, by acting on AgRP/NPY-expressing neurons, leptin inhibits the synthesis of AgRP and NPY [83,86]. Single-minded 1 (SIM1), a transcription factor expressed in the PVN that is crucial for its correct development, also mediates melanocortin action and participates in body weight regulation [87]. SIM1-expressing neurons in the hypothalamus co-localize with populations expressing the brain-derived neurotropic factor (BDNF), and together these factors contribute to neuronal pathways controlling energy balance and appetite suppression [88]. BDNF appears to act by binding and activating the neurotrophic tyrosine kinase receptor (TRKB/NTRK2), expressed in the ventromedial hypothalamus (VMH), downstream of the MC4R signaling. MC4R signaling could impact on BDNF expression in the VMH [89,90], which conveys an anorexigenic signal and influences food intake [91].

Figure 1.

The leptin-melanocortin pathway. Leptin, released by adipocytes, acts via the LEPR, present on the surface of the ARC neurons, promoting POMC synthesis. POMC is cleaved by PCSK1, yielding α-MSH. α-MSH is released by the POMC axon terminals to activate MC4R-expressing neurons at the PVN, which inhibits food intake. On the other hand, leptin suppresses the AgRP/NPY synthesis. SIM1 contributes to the correct development of PVN and mediates melanocortin action. BDNF affects energy homeostasis by conveying an anorexigenic signal and is thought to act by binding and activating TRKB/NTRK2. GLP-1 is released by the gastrointestinal tract and binds to hypothalamic GLP-1R to potentially stimulate POMC-expressing neurons and inhibit AgRP/NPY-expressing neurons to control food intake. GHRL promotes food intake by activating GHSR in the AgRP/NPY-expressing neurons. UCP2, expressed in the POMC and AgRP/NPY neurons, modulates neuronal function. (↓) downregulation; (↑) upregulation; (+) promotion; (−) inhibition.

Other hormones, such as peptide hormones secreted by the gastrointestinal system, are also involved in appetite regulation via this neuroendocrine pathway. One example is GLP-1, an anorexigenic hormone released after food intake that acts through the GLP-1R in the ARC and PVN hypothalamic nuclei [78]. GLP-1R is likely involved in the activation of POMC-expressing neurons and inhibition of AgRP/NPY-expressing neurons, the pathway through which the pharmacological use of GLP-1RA induces body weight reduction for obesity treatment [92]. On the other hand, ghrelin (GHRL) is an orexigenic hormone, which is predominantly secreted by the enteroendocrine P/D₁ cells at the gastric fundus [93]. GHRL binds to the growth hormone secretagogue receptor (GHSR), expressed at the ARC, which promotes growth hormone release besides participating in body weight regulation via several behavioral and metabolic mechanisms [94]. GHRL promotes food intake by activating GHSR at the AgRP/NPY-expressing neurons of the ARC, which may result in the inhibition of POMC-expressing neurons [95]. The uncoupling protein 2 (UCP2) gene is suggested to be a player in energy homeostasis, lipid metabolism, and body weight regulation. It is expressed by several tissues, including the adipose tissue, and might contribute to fat accumulation [96]. Since UCP2 is expressed in the POMC and AgRP/NPY neurons, it is likely involved in the leptin-melanocortin pathway [97]. In the presence of high glucose levels, UCP2 reduces ATP levels and alters POMC neurons’ activity. Conversely, when glucose levels are low, UCP2 enhances AgRP/NPY neuronal activity. Moreover, UCP2 ablation contributes to reducing fasting and ghrelin-induced food intake, by increasing reactive oxygen species (ROS) levels, which in turn decreases AgRP/NPY neuronal activation [98].

Genetic variants involved in the leptin-melanocortin pathway not only play a critical role in regulating body weight but also appear to influence the effectiveness of WL interventions, as these variations can affect how individuals respond to lifestyle-based interventions (such as diet and exercise), bariatric surgery, and even pharmacological treatments. As a result, they are increasingly recognized as important predictive biomarkers for determining the likelihood of success or failure in WL strategies, highlighting their potential in guiding personalized obesity management.

4.2.1. Leptin receptor (LEPR)

Genetic variants located at the LEPR have been associated with obesity [99]. The LEPR missense variant p. (Gln223Arg) (rs1137101) has a functional impact on the activity and structure of the LEPR, influencing signal transduction and binding affinity, changes that confer a heightened risk for T2D [100]. The LEPR variant also seems to influence the outcomes of WL interventions. Young males with obesity carrying the Gln²²³ allele were more likely to lose weight after an exercise intervention [101]. In contrast, the Arg²²³ allele has been associated with a higher saturated fat consumption and increased risk of obesity, suggesting a potential genotype–nutrient interaction [102]. This variant was also associated with less effective WL postoperatively, with Gln²²³/Gln²²³ individuals experiencing greater WL one year after RYGB [103].

4.2.2. Neuropeptide Y (NPY)

The T > C replacement (rs16147) in the promoter region of the NPY gene impacts gene expression, with the C allele being linked to higher NPY expression [104]. Children homozygous for the T allele exhibited higher BMI [105]. This NPY variant also appears to affect the effectiveness of lifestyle interventions for WL, with C allele carriers exhibiting a greater decrease in waist circumference, whereas T allele carriers presented a higher tendency for abdominal fat regain, when exposed to a high-fat diet [106]. After BPD, T allele carriers exhibited an earlier decrease in obesity-related biochemical parameters, such as glucose, fasting insulin, and HOMA-IR, suggesting a potential link with a faster metabolic response, even though no differences in WL were observed between genotypes [107].

4.2.3. Proopiomelanocortin (POMC)

The G > A replacement (rs1042571), located in the 3’ UTR region of the POMC gene, was found to be associated with BMI in individuals of European ancestry [108], as well as with a fat-to-protein ratio, suggesting that the POMC variant may also influence food preferences [109]. Furthermore, previous data revealed that this variant is associated with greater WL up to one year after RYGB surgery [110].

4.2.4. Melanocortin-4 receptor (MC4R)

Several MC4R variants that impair the functional properties of the receptor, thereby influencing the melanocortinergic pathway, were identified as being linked to familial early-onset severe obesity [111]. Carriers of three or four risk alleles of the MC4R rs17782313(C) and FTO rs9939609(A) variants were associated with higher BMI [112], while the co-occurrence of MC4R rs17782313/rs12970134 and FTO rs9939609 variants was associated with obesity in Chinese children and adolescents [113]. Several MC4R variants were shown to have an impact on the WL outcomes after bariatric surgery [114]. The T > C substitution (rs17782313) is located in the intronic region of the MC4R gene. Both homozygous CC and heterozygous CT individuals for this variant have been linked to WL failure after RYGB in women, defined as the maintenance of a BMI above 35 kg/m² at twenty-four months after surgery [115]. In contrast, the T > G replacement (rs52820871) of the MC4R gene (p. (Ile251Leu)) is associated with a higher MC4R constitutional activity through the modification of downstream intracellular events related to GPCR cAMP signal transduction [116]. This variant was linked to better WL outcomes after dietary intervention before surgery, as well as following surgery [117].

4.2.5. Ghrelin (GHRL)

The G > T substitution (rs696217) of the GHRL gene (p. (Leu72Met)), located in the preproghrelin region, outside the mature ghrelin, was found to be more frequent in individuals with obesity [118]. Heterozygous individuals exhibited greater WL fifty-two weeks after RYGB, with Met⁷² carriers presenting a more pronounced reduction in BMI [119].

4.2.6. Growth hormone secretagogue receptor (GHSR)

GHSR gene is a locus strongly linked to several phenotypes associated with obesity and is regarded as a valuable marker for metabolic disorders [120]. The G > C (rs490683) and C > T (rs9819506) substitutions of the GHSR gene are located in the promoter region [121]. Matzko et al. showed a decrease of almost 20% in promoter activity in a mouse model carrying the CC genotype of rs490683. According to the authors, decreased GHSR1 expression reduces the net signaling from ghrelin binding, potentially allowing more favorable WL outcomes [122]. Indeed, homozygous CC (rs490683) achieved greater WL after a diet and exercise intervention, while homozygous AA (rs9819506) showed the lowest body weight [121]. Additionally, homozygous CC (rs490683) experienced greater WL following RYGB, whereas homozygous CC (rs9819506) had a lower WL [122].

4.2.7. Glucagon like-1 peptide receptor (GLP-1R)

The missense variant p. (Gly168Ser) (rs6923761) in the GLP-1R gene is associated with altered GLP-1R function [123]. The Ser¹⁶⁸ allele was found to be more frequent in individuals with excessive BMI, whereas the Gly¹⁶⁸/Gly¹⁶⁸ genotype was associated with a lower risk of excessive body weight [124]. In contrast, other studies have found that Ser¹⁶⁸ carriers tended to have a lower BMI and fat mass [125]. Interestingly, Ser¹⁶⁸ carriers exhibited a greater reduction in anthropometric parameters [126], including body weight and fat mass, after hypocaloric diets [127] or treatment with liraglutide [128]. Although, Gly¹⁶⁸/Gly¹⁶⁸ carriers experienced a more pronounced decrease in waist circumference and overall a better WL outcomes after BPD [129].

4.2.8. Brain-derived neurotrophic factor (BDNF)

The BDNF p. (Val66Met) variant (rs6265) results in a missense substitution that modifies the intracellular processing, packaging, and trafficking of pro-BDNF, which eventually interferes with the secretion of mature BDNF [130]. The Met⁶⁶/Met⁶⁶ genotype was linked to a lower BMI in healthy adults [131], as well as children, and a lower postprandial glucose excursion in post-pubertal individuals [132]. These findings suggest a possible relationship between this variant and BMI. This variant has also been associated with the WL outcomes of bariatric surgery, since carriers of the Met⁶⁶ allele experienced greater WL following RYGB or SG, when compared to homozygous Val⁶⁶/Val⁶⁶ [133].

4.2.9. Uncoupling protein 2 (UCP2)

Genetic variants in the UCP2 gene have the potential to affect metabolic rate and may serve as a risk factor for obesity [134]. The UCP2 p. (Ala55Val) variant (rs660339) was shown to have a relevant impact on WL following bariatric surgery [135], with carriers of the Val⁵⁵ allele exhibiting a greater WL six months after LGB [136], as well as one year after RYGB [137].

Another relevant variant at this gene, the C > T replacement (rs659366), located upstream of the transcription start site that influences promoter activity [138], was also shown to impact the outcomes of WL interventions. Specifically, women carrying the G allele experienced greater WL than those with the AA genotype in response to a very low calorie diet [139]. Furthermore, carriers of the AA genotype displayed higher BMI twelve months after RYGB [140].

5. Overview of the impact of obesity-linked genetic variants on weight loss outcomes

This section offers an overview of the available evidence on the influence of genetic variants for the outcomes of different WL strategies, which is predominantly focused on lifestyle-based interventions and bariatric surgery (Figure 2). Among the identified genetic variants, the ones on leptin and ghrelin receptor (LEPR [101,103,163], GHSR [121,122]) were demonstrated to influence the WL outcomes of both lifestyle and surgical interventions. Moreover, variants in other genes that participate in the leptin-melanocortin pathway were also demonstrated to impact WL after bariatric surgery, among which are the POMC rs1042571 [110], UCP2 rs660339 [114,136,137] and GHRL rs696217 [119] as important examples. Another interesting finding lies in the observation that both allelic forms of a genetic variant can have a distinct impact in the outcomes of different WL approaches. A compelling example is the rs9819506 variant at the GHSR gene, with homozygous AA displaying the lowest body weight after diet/exercise [121], while homozygous CC exhibiting worse WL response after bariatric surgery [122], supporting the hypothesis that the different genotypes could be related with the differential expression of the receptor and influence ghrelin signaling. It is important to note the differences between these two studies when comparing their outcomes in response to distinct WL approaches, while accounting for potential biases and random effects.

Figure 2.

Summary of genetic variants associated with better or worse outcomes after WL interventions. For additional information regarding the association between these genetic variants and the outcomes after distinct WL interventions, consult the Supplementary Table 1.

6. Other genetic variants with potential influence on weight loss intervention outcomes

Beyond the well-characterized genes associated with obesity, such as FTO, or involved in the leptin-melanocortin pathway, several other genetic variants may play a significant role in determining individual responses to various WL strategies, including lifestyle-based interventions, pharmacological treatments, and bariatric surgery. Among these are the Lysophospholipase-like 1 (LYPLAL1) gene that encodes the lysophospholipase-like protein 1 suggested to act as a triacylglycerol lipase in the adipose tissue [164]. Variants near LYPLAL1 have been associated with fat distribution and waist-to-hip ratio [165]. Moreover, TT carriers of rs4846567 presented better outcomes after RYGB, with lower hunger scores and a 7% greater BMI reduction compared to other genotypes [166]. Another gene is the Estrogen receptor 1 (ESR1), also known as ER-α, which is expressed in the hypothalamus and amygdala [167], and is involved in estrogen signaling as well as lipid metabolism. ESR1 variants have been associated with several diseases, including obesity [168]. The rs712221 variant of the ESR1 was shown to influence WL after bariatric surgery, SG or laparoscopic mini-gastric bypass (LMGB), with individuals homozygous for the TT genotype presenting a greater WL when compared to A allele carriers [136,169]. Additionally, the TT genotype of the 5-hydroxytryptamine 2C receptor (5-HTC2) rs3813929 [170] and the G allele of the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 [171] variants were also associated with better WL outcomes after bariatric surgery. By contrast, the C allele of the CD40 ligand gene (CD40L) rs1126535 [119] and the T allele of the FK506 binding protein 5 (FKBP5) rs1360780 [172,173] were linked to worse WL responses following bariatric surgical procedures. Interestingly, the 5-HT2C is the target of several antipsychotic drugs that act as serotonin receptor antagonists, such as clozapine, olanzapine and risperidone, which are associated with weight gain due to heightened food intake as a side effect [174]. Overall, this suggests that 5-HT2C has also been involved in food intake regulation and could play a role in promoting weight gain [175].

7. Recent findings in the genetics of obesity

The knowledge on the genetics of obesity has been constantly evolving as more genomes have been sequenced and more genetic variants linked to obesity are being uncovered, such as Fibroblast Growth Factor Receptor Substrate 3 (FRS3) [176], Myotubularin-Related Protein 3 (MTMR3) [177], Bassoon (BSN) [178]. Among these is the DENN domain containing 1 B (DENND1B), one of the most recently identified obesity-linked genes in a GWAS study, which has been associated with higher body fat in humans and dogs, suggesting a potential role in fat accumulation across species [179]. In fact, DENND1B modulates MC4R activity and is likely to play a crucial role in energy homeostasis. Moreover, this discovery highlights the value of comparative studies in identifying disease-associated alleles that are conserved across species, emphasizing their potential in uncovering shared genetic factors underlying complex disease conditions, such as obesity [180].

8. Limitations

The current review has some limitations that are acknowledged here. At this stage, it is important to emphasize that the small number of studies exploring the association between genetic variants and WL strategies still restricts a comprehensive understanding of these relationships. Future studies should focus on understanding the mechanisms underlying the link between these variants and the genetic background on the effectiveness of WL interventions, including pharmacological treatments for which there is no information in public domains. Understanding key cellular and molecular pathways can lead to the recognition of potential novel targets for pharmacological interventions. Additionally, although this paper focused predominantly on the impact of each gene variant per se, the synergistic effect of multiple variants within and between genes is likely to play a substantial role in the genotype–phenotype relationship and should not be underestimated. Given the multifactorial nature of the disease, future studies should also address the influence of environmental factors in modulating the impact of genetic variants on the outcomes of WL interventions. Lastly, several factors should be considered when assessing variability of response to WL interventions, such as the type of WL intervention used, including the type of lifestyle, pharmacological, or even bariatric surgery procedure, the duration of follow-up, as well as the presence of obesity-associated complications and genetic predisposition linked to WL resistance.

9. Concluding remarks

Obesity is a highly prevalent disease with a significant impact on the health of affected individuals, as well as on healthcare systems worldwide. Obesity management involves different WL approaches and encompasses lifestyle-based interventions, with diet and exercise, pharmacotherapy, or bariatric surgery, as appropriate according to the disease severity. In this review, we delved into how some genetic variants could impact the outcomes of distinct WL interventions. Individuals possessing these variants exhibited worse (e.g. MC4R rs17782313) or better (e.g. GHRL rs696217, POMC rs1042571, BDNF rs6265) WL outcomes after bariatric surgery, and other genetic variants influenced the outcomes of both lifestyle-based and/or surgical approaches (e.g. FTO rs9939609, GHSR rs490683, LEPR rs1137101). The majority of the genetic variants were found in genes linked to the leptin-melanocortin pathway, involved in energy homeostasis regulation, by modulating food intake and energy expenditure. These variants are highly relevant and may serve as potential prognostic biomarkers for predicting the success or failure of obesity treatment approaches. Further, these findings highlight the potential use of a genetic screening before initiating an obesity management approach. Through the identification of key variants and the genetic profile, clinicians could guide their choice and better predict the responsiveness of a patient to a specific WL approach, whether it is a lifestyle-based intervention, pharmacotherapy, or bariatric surgery. Further studies linking genotype data with long-term clinical outcomes are needed to establish evidence-based guidelines for implementation. Understanding how an individual's genetic background influences the outcomes of WL interventions is of utmost importance for developing more precise and personalized strategies, aimed at achieving more effective and long-lasting results, moving toward precision medicine in obesity management.

CRediT authorship contribution statement

Mariana Santos-Pereira: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Marta Guimarães: Writing – review & editing, Supervision, Project administration. Mariana P. Monteiro: Writing – review & editing, Data curation. Sofia S. Pereira: Writing – review & editing, Supervision, Project administration, Funding acquisition, Data curation, Conceptualization. Luísa Azevedo: Writing – review & editing, Supervision, Project administration, Funding acquisition, Data curation, Conceptualization.

Funding sources

This study was supported through national funding from the Foundation for Science and Technology – FCT within the projects: UID/215/2025, LA/P/0064/2020 (DOI: 10.54499/LA/P/0064/2020), PTDC/MEC-CIR/3615/2021 (DOI: 10.54499/PTDC/MEC-CIR/3615/2021), and the PhD studentship 2024.05899.BD.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Data availability

No data was used for the research described in the article.