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Exploring the role of testosterone upon adiposity and cardiovascular risk markers in men with severe obesity

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Metab Target Organ Damage 2024;4:4.
10.20517/mtod.2023.40 |  © The Author(s) 2024.
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Abstract

A prominent endocrine disorder linked to unhealthy lifestyle behaviors and increased visceral adiposity is Male Obesity Secondary Hypogonadism (MOSH). The pathogenesis of MOSH remains under investigation. However, recent evidence supports a direct role of leptin in affecting Leydig cells, reducing testosterone production, and increasing appetite. Conversely, testosterone deficiency is associated with comorbidities like hypertension, diabetes, and nonalcoholic fatty liver disease. A recently published study entitled “Relationship between sex hormones, markers of adiposity and inflammation in male patients with severe obesity undergoing bariatric surgery” describes evidence supportive of an inverse association between testosterone and serum leptin as well as levels of c-reactive protein (CRP) and IL-6, as well as a correlation between body mass index and CRP. The same study also provides novel insight retrieved from their in vitro findings, which reveal that testosterone exposure influences the expression of genes associated with adiposity, like fatty acid binding protein 4, peroxisome proliferation-activated receptor γ (PPARγ), leptin, and adiponectin, as well as von Willebrand factor, in human-derived adipocytes. Overall, the latest evidence highlights the importance of early identification of hypogonadism in obese males and the potential benefits of testosterone supplementation in alleviating complications associated with obesity, particularly chronic inflammation. These observations underscore the need for a holistic approach to managing severe obesity, addressing hormonal and inflammatory factors to reduce its overall burden on health.

Keywords

Testosterone, male obesity secondary hypogonadism, adipocytes, von Willebrand factor

Obesity and metabolic syndrome are medical conditions linked to an array of hormonal irregularities, often underestimated but significantly impacting the well-being of affected individuals[1,2]. The predominant endocrine disorder associated with unhealthy lifestyle behaviors and increased visceral adiposity prevalence often manifests as temporary gonadal dysfunction[3-5]. This condition, known as MOSH, may resolve in parallel with the resolution of metabolic disorders and the amelioration of insulin resistance after a significant and enduring weight loss[2,6,7]. The hormonal imbalance in cases with MOSH is characterized by organic hypothalamic-pituitary-testicular axis suppression with the ensuing presence of low testosterone levels and elevated 17-β-estradiol concentrations[8].

As per the latest guidelines of the European Academy of Andrology (EAA), secondary hypogonadism can be classified as organic or functional, while it can also be related to altered testosterone bioactivity[7]. Functional testicular failure can occur in individuals aged over 70 years, particularly when accompanied by concurrent health conditions[7]. In any case, comorbidities such as acute or critical illness, malnutrition, and obesity, and drugs like opioids, glucocorticoids, and androgens or anabolic-androgenic steroids are known to be associated with secondary hypogonadism[7,9]. In this context, MOSH also represents a subgroup of secondary hypogonadism[10].

While the exact mechanisms at play remain to be clarified, the role of aromatase as a cause of hypogonadism is still not fully understood, and inflammatory activity may be the main player[11,12]. This enzyme, predominantly found in adipocytes, enhances the conversion of circulating testosterone into 17-β-estradiol, ultimately contributing to the development of MOSH[13,14]. However, this hypothesis has limitations, as it does not consistently explain why a decrease in testosterone is not invariably accompanied by an increase in 17-β-estradiol levels in clinical practice[13,14]. Elevated estrogen levels diminish the pulse amplitude of luteinizing hormone (LH) and potentially promote adipogenesis directly, resulting in heightened accumulation of subcutaneous, ectopic, and visceral fat[15]. Consequently, the heightened expression of aromatase due to obesity could contribute to additional peripheral fat buildup, both by amplifying estrogen levels and diminishing testosterone production induced by LH[15,16]. Heightened estrogen is exerting an adverse effect on erectile function, leading to increased vascular permeability in the mature penis, and a reported increase in the prevalence of erectile dysfunction[17].

Recent evidence highlighted the role of leptin, a well-documented regulator of gonadotrophin-releasing neurons[18], typically produced by the white adipose tissue. This hormone mediator acts directly on Leydig cells, downregulating their steroidogenic capacity[19]. On the other hand, hyperleptinemia and the ensuing leptin resistance further decrease testosterone production, a hormonal alteration that contributes to increasing food intake and appetite[20]. On the contrary, a growing body of evidence also supports the role of hypogonadism in regulating body fat accumulation. Testosterone deficiency is likely attributed to comorbidities such as hypertension, diabetes mellitus, visceral obesity, and metabolic syndrome[21,22]. Data from patients treated with androgen deprivation therapy for prostate cancer highlighted that antiandrogen treatment increases the body mass index and consequently contributes to the development of obesity[23]. Testosterone deficiency is also associated with the risk of developing nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea[24,25].

The recent study by Di Vincenzo et al., published in this journal, aimed to investigate the intricate connection between obesity and hypogonadism and the role of low-grade inflammation as a possible mediator of this relationship[26]. The findings offer valuable insights into the potential factors contributing to obesity-related complications in males. The clinical arm of the study was conducted on a small cohort of 24 patients with grade III obesity undergoing bariatric surgery (mean age of 43 ± 8 years). The in vitro arm of the study involved differentiated human adipocytes, which were incubated in a testosterone environment, after which the expression of markers related to adiposity was evaluated. The results of the clinical arm of the study[26] described a strong correlation between the body mass index (BMI) and high-sensitivity C-reactive protein (hsCRP). More importantly, the investigators described an inverse association between levels of testosterone and hsCRP, HOMA (homeostasis model assessment) index, leptin, and von Willebrand factor concentrations[26]. Furthermore, the in vitro arm of the study demonstrated that exposure to testosterone can influence the gene expression of markers associated with adiposity, such as fatty acid binding protein 4 (FABP-4), PPARγ, leptin, and adiponectin, in human-derived adipocytes. This effect was partially reversed when the antiandrogen flutamide was introduced.

The finding of an association between obesity and low-grade chronic inflammation, as reported in the study by Di Vincenzo et al., is in line with earlier observations[26]. Results retrieved from in vitro studies described that in states of increased energy storage, white adipocytes react with abnormal expansion, leading to hypoxia and remodeling-induced senescence[27]. These states of hypoxia and senescence play a pivotal role in initiating and perpetuating a state of chronic, low-grade inflammation. In such circumstances, adipocytes encounter endoplasmic reticulum stress and heightened production of reactive oxygen species (ROS)[27]. Dysfunctional adipocytes further exacerbate the situation by releasing inflammatory cytokines while compromising the production of protective adipokines, such as adiponectin[27]. These adipocytokines can mediate the adverse effects of obesity, particularly on the cardiovascular system and endothelial function, further underscoring the intricate relationship between hormonal changes and the broader health implications associated with obesity[28,29].

The association between endogenous testosterone levels and metabolic markers described in the study by Di Vincenzo et al. is supported by clinical data retrieved from observational studies[26]. A meta-analysis of 37 observational studies (43,041 participants, mean age of 63.5 years, follow-up of 333 weeks) reported that low levels of testosterone were significantly associated with a 1.26-times higher risk of predicted overall mortality, 1.54-times higher risk of cardiovascular mortality, and 1.17-times higher risk of cardiovascular morbidity[30]. Furthermore, low testosterone levels affect 30% of patients with type 2 diabetes[31]. In any case, a large number of studies described that the link between testosterone deficiency and diabetes mellitus is bidirectional[32,33].

A growing body of evidence also supports an association between exogenous testosterone administration and parameters of the metabolic profile. The T4DM trial (Testosterone for Diabetes Mellitus), a randomized, double-blind, placebo-controlled phase 3b trial, suggests that implementing a lifestyle program alongside two years of testosterone supplementation in overweight men with low testosterone levels, yet no signs of pathological hypogonadism has the potential to reverse type 2 diabetes (T2DM)[33]. Furthermore, a mediation analysis of the same population showed that a significant portion of the impact of testosterone treatment was attributed primarily to changes in fat mass, skeletal muscle mass, and grip strength[34]. Furthermore, testosterone treatment is improving body composition by increasing the total fat-free mass in hypogonadal men, and the effect is more pronounced in those with testosterone levels below the diagnostic cut-off for the diagnosis of hypogonadism (< 264 ng/dL)[35]. In a very long-term observational registry study, exogenous testosterone administration has been demonstrated to achieve remission of T2DM[36] and completely prevent progression from prediabetes to T2DM[37]. The body composition and musculoskeletal parameters adversely affected by low testosterone levels may mirror sarcopenia, which is also known to be associated with NAFLD[38]. Moreover, the link between steatotic liver disease and low testosterone levels has been described in human and animal studies. In fact, studies in castrated rodents showed that testosterone supplementation can sufficiently ameliorate the proportion of hepatic steatosis induced by a high-fat diet. Moreover, low testosterone levels in males have been linked with steatotic liver disease, independently of type 2 diabetes mellitus, insulin resistance, and BMI[39].

The link between androgenicity and prothrombotic parameters has been supported by the results of earlier in vivo and human evidence. The earlier in vivo study by Alqahtani et al. assessed the effect of testosterone deficiency and replacement upon prothrombotic and antifibrinolytic parameters[40]. This study showed that TD induces hypercoagulation and inhibits platelet aggregation and fibrinolysis, effects that can be reversed by testosterone supplementation[40]. Similar results were reported in a human study when lower androgenicity was related to higher levels of prothrombotic factors such as fibrinogen and factor VII concentrations. At the same time, men with low levels of sex hormone-binding globulin were found to have higher levels of plasminogen activator inhibitor-1, both antigen and activity[41]. The clinical arm of Di Vincenzo et al.’s study reported a significant inverse association between testosterone levels and von Willebrand factor levels[26]. Considering the role of heightened von Willebrand factor levels during acute coronary events[42], treatment with testosterone appears even more encouraging in states where cardiovascular protection is desired.

A growing body of evidence describes the role of molecules involved in adipogenesis, which appear to regulate adipocyte differentiation and activity, including leptin, adiponectin, PPARγ, and FABP-4. Leptin regulates the intracellular signaling in both preadipocytes and adipocytes, fostering adipogenesis and influencing the release of inflammatory mediators. Additionally, leptin reinstates adipogenesis even in the absence of insulin[43]. Adiponectin is a well-accepted biomarker of adipocyte differentiation in human mesenchymal stromal cells. The effect of adiponectin appears to be mediated by PPARγ, which modulates its activation[44-46]. PPARγ is one of the major adipogenic transcription factors, which works together with other epigenomic regulators and transcription factors, aiming to activate the adipocyte genes required to regulate the terminal differentiation of preadipocytes[47]. FABP-4 has been demonstrated to act as the downstream regulator of PPARγ, which plays an important role in the regulation of β cell function[48,49].

Additionally, the in vitro arm of Di Vincenzo et al.’s study (2023) highlighted that testosterone incubation can downregulate the gene expression of various markers, such as leptin and adiponectin, but also transcription factors like PPARγ and FABP-4, in human differentiated adipocytes[26]. These observations concerning the effect of testosterone and the regulation of adipocyte gene expression are not surprising. Earlier data showed that testosterone administration can stimulate the expression of the two salmon leptin-a genes in a dose-dependent manner, as observed in Atlantic salmon parr hepatocytes[50]. The expression of androgen receptors has been demonstrated by in vitro studies of human preadipocytes and mature adipocytes[51-53]. Earlier evidence from differentiated preadipocytes retrieved from male rat fat pads also showed that the density of androgen receptors is regulated by testosterone[52]. On the contrary to the above, mature SGBS (Simpson-Golabi-Behmel syndrome) preadipocytes incubated in testosterone did not result in a higher expression and secretion of adiponectin mRNA or higher synthesis of intracellular adiponectin multimer proteins[54].

The study by Di Vincenzo et al. has significant implications, as their findings explain various interactions between testosterone and cardiometabolic risk markers, which include insulin resistance, chronic inflammation, and predisposition towards a more thrombotic profile[26]. In more clinical terms, this study highlights the importance of early identification of males affected by hypogonadism, including those affected by states of obesity and early initiation of testosterone supplementation. By addressing this hormonal imbalance, it may be possible to alleviate some of the complications related to obesity, particularly the chronic inflammatory state. These findings emphasize the need for a holistic approach to managing severe obesity, considering hormonal and inflammatory factors to reduce the disease's overall burden.

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Authors’ contributions

The author contributed solely to the article.

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None.

Conflicts of interest

The author declared that there are no conflicts of interest.

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Copyright

© The Author(s) 2024.

REFERENCES

1. Fernandez CJ, Chacko EC, Pappachan JM. Male obesity-related secondary hypogonadism-pathophysiology, clinical implications and management. Eur Endocrinol 2019;15:83-90.

2. Leisegang K, Henkel R, Agarwal A. Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system. Am J Reprod Immunol 2019;82:e13178.

3. Stanford FC, Tauqeer Z, Kyle TK. Media and its influence on obesity. Curr Obes Rep 2018;7:186-92.

4. Camacho EM, Huhtaniemi IT, O'Neill TW, et al; EMAS Group. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol 2013;168:445-55.

5. Shi Z, Araujo AB, Martin S, O'Loughlin P, Wittert GA. Longitudinal changes in testosterone over five years in community-dwelling men. J Clin Endocrinol Metab 2013;98:3289-97.

6. Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update 2017;23:390-408.

7. Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology 2020;8:970-87.

8. Calderón B, Gómez-Martín JM, Vega-Piñero B, et al. Prevalence of male secondary hypogonadism in moderate to severe obesity and its relationship with insulin resistance and excess body weight. Andrology 2016;4:62-7.

9. Wu FC, Tajar A, Pye SR, et al; European Male Aging Study Group. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008;93:2737-45.

10. Bellastella G, Menafra D, Puliani G, Colao A, Savastano S; Obesity Programs of nutrition. How much does obesity affect the male reproductive function? Int J Obes Suppl 2019;9:50-64.

11. Rubinow KB. Estrogens and body weight regulation in men. In: Mauvais-jarvis F, editor. Sex and gender factors affecting metabolic homeostasis, diabetes and obesity. Cham: Springer International Publishing; 2017. pp. 285-313.

12. Dhindsa S, Furlanetto R, Vora M, Ghanim H, Chaudhuri A, Dandona P. Low estradiol concentrations in men with subnormal testosterone concentrations and type 2 diabetes. Diabetes Care 2011;34:1854-9.

13. Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Clin Endocrinol 2013;78:330-7.

14. Cohen PG. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection. Med Hypotheses 2001;56:702-8.

15. Birzniece V. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013;369:2455.

16. Xu X, Sun M, Ye J, et al. The effect of aromatase on the reproductive function of obese males. Horm Metab Res 2017;49:572-9.

17. Schulster M, Bernie AM, Ramasamy R. The role of estradiol in male reproductive function. Asian J Androl 2016;18:435-40.

18. Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 2009;150:2805-12.

19. Marcouiller F, Jochmans-Lemoine A, Ganouna-Cohen G, et al. Metabolic responses to intermittent hypoxia are regulated by sex and estradiol in mice. Am J Physiol Endocrinol Metab 2021;320:E316-25.

20. Carrageta DF, Oliveira PF, Alves MG, Monteiro MP. Obesity and male hypogonadism: tales of a vicious cycle. Obes Rev 2019;20:1148-58.

21. Genchi VA, Rossi E, Lauriola C, et al. Adipose tissue dysfunction and obesity-related male hypogonadism. Int J Mol Sci 2022;23:8194.

22. Dimopoulou C, Goulis DG, Corona G, Maggi M. The complex association between metabolic syndrome and male hypogonadism. Metabolism 2018;86:61-8.

23. Mangiola S, Stuchbery R, McCoy P, et al. Androgen deprivation therapy promotes an obesity-like microenvironment in periprostatic fat. Endocr Connect 2019;8:547-58.

24. Kim S, Kwon H, Park JH, et al. A low level of serum total testosterone is independently associated with nonalcoholic fatty liver disease. BMC Gastroenterol 2012;12:69.

25. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23:490-4.

26. Di Vincenzo A, Crescenzi M, Granzotto M, et al. Relationship between sex hormones, markers of adiposity and inflammation in male patients with severe obesity undergoing bariatric surgery. Metab Target Organ Damage 2023;3:12.

27. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol 2021;320:C375-91.

28. Liu L, Shi Z, Ji X, et al. Adipokines, adiposity, and atherosclerosis. Cell Mol Life Sci 2022;79:272.

29. Koliaki C, Liatis S, Kokkinos A. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism 2019;92:98-107.

30. Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Endogenous testosterone levels and cardiovascular risk: meta-analysis of observational studies. J Sex Med 2018;15:1260-71.

31. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89:5462-8.

32. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab 2011;96:2341-53.

33. Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol 2021;9:32-45.

34. Robledo KP, Marschner IC, Handelsman DJ, et al. Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the testosterone for prevention of type 2 diabetes mellitus trial. Eur J Endocrinol 2023;188:613-20.

35. Deepika F, Ballato E, Colleluori G, et al. Baseline testosterone predicts body composition and metabolic response to testosterone therapy. Front Endocrinol 2022;13:915309.

36. Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes Obes Metab 2020;22:2055-68.

37. Yassin A, Haider A, Haider KS, et al. Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry study. Diabetes Care 2019;42:1104-11.

38. Arrese M, Cabello-Verrugio C, Arab JP, et al. Sarcopenia in the setting of nonalcoholic fatty liver. Metab Target Organ Damage 2022;2:2.

39. Nasr P, Jönsson C, Ekstedt M, Kechagias S. Non-metabolic causes of steatotic liver disease. Metab Target Organ Damage 2023;3:19.

40. Alqahtani SA, Alhawiti NM. Administration of testosterone improves the prothrombotic and antifibrinolytic parameters associated with its deficiency in an orchidectiomized rat model. Platelets 2019;30:624-30.

41. De Pergola G, De Mitrio V, Sciaraffia M, et al. Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism 1997;46:1287-93.

42. Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008;117:1449-59.

43. Palhinha L, Liechocki S, Hottz ED, et al. Leptin induces proadipogenic and proinflammatory signaling in adipocytes. Front Endocrinol 2019;10:841.

44. Astapova O, Leff T. Chapter Six - Adiponectin and PPARγ: cooperative and interdependent actions of two key regulators of metabolism. Adiponectin. Elsevier; 2012. pp. 143-62.

45. Shan T, Liu W, Kuang S. Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 2013;27:277-87.

46. Yang W, Yang C, Luo J, Wei Y, Wang W, Zhong Y. Adiponectin promotes preadipocyte differentiation via the PPARγ pathway. Mol Med Rep 2018;17:428-35.

47. Lee JE, Schmidt H, Lai B, Ge K. Transcriptional and epigenomic regulation of adipogenesis. Mol Cell Biol 2019;39:e00601-18.

48. Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 2019;20:242-58.

49. Prentice KJ, Saksi J, Robertson LT, et al. A hormone complex of FABP4 and nucleoside kinases regulates islet function. Nature 2021;600:720-6.

50. Trombley S, Rocha A, Schmitz M. Sex steroids stimulate leptin gene expression in Atlantic salmon parr hepatocytes in vitro. Gen Comp Endocrinol 2015;221:156-64.

51. Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids. Am J Physiol 1998;274:C1645-52.

52. De Pergola G, Xu XF, Yang SM, Giorgino R, Bjorntorp P. Up-regulation of androgen receptor binding in male rat fat pad adipose precursor cells exposed to testosterone: study in a whole cell assay system. J Steroid Biochem Mol Biol 1990;37:553-8.

53. Xu X, De Pergola G, Björntorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells. Endocrinology 1990;126:1229-34.

54. Horenburg S, Fischer-Posovszky P, Debatin KM, Wabitsch M. Influence of sex hormones on adiponectin expression in human adipocytes. Horm Metab Res 2008;40:779-86.

Cite This Article

OAE Style

Armeni E. Exploring the role of testosterone upon adiposity and cardiovascular risk markers in men with severe obesity. Metab Target Organ Damage 2024;4:4. http://dx.doi.org/10.20517/mtod.2023.40

AMA Style

Armeni E. Exploring the role of testosterone upon adiposity and cardiovascular risk markers in men with severe obesity. Metabolism and Target Organ Damage. 2024; 4(1): 4. http://dx.doi.org/10.20517/mtod.2023.40

Chicago/Turabian Style

Armeni, Eleni. 2024. "Exploring the role of testosterone upon adiposity and cardiovascular risk markers in men with severe obesity" Metabolism and Target Organ Damage. 4, no.1: 4. http://dx.doi.org/10.20517/mtod.2023.40

ACS Style

Armeni, E. Exploring the role of testosterone upon adiposity and cardiovascular risk markers in men with severe obesity. Metab Target Organ Damage. 2024, 4, 4. http://dx.doi.org/10.20517/mtod.2023.40

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© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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