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Revista chilena de nutrición

versión On-line ISSN 0717-7518

Rev. chil. nutr. vol.46 no.5 Santiago oct. 2019

http://dx.doi.org/10.4067/S0717-75182019000500622 

Review Article

The relationship between chronic inflammation associated with obesity and vitamin D deficiency

Relación entre inflamación crónica asociada a obesidad y déficit de vitamina D

Carla Guzmán1  * 

Paula Fredes2 

Carlos Manterola3  4 

1Carrera Nutrición y Dietética, Facultad Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Concepción, Chile.

2Nutricionista Programa Cardiovascular, Centro de Salud Familiar Victor Manual Fernández, Concepción, Chile.

3Departamento de Cirugía, Universidad de La Frontera, Temuco, Chile.

4Programa de Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco, Chile

SUMMARY

Obesity is characterized by an abnormal production of adipocytokines, generating chronic inflammation associated in turn with endothelial dysfunction, atherosclerosis and insulin resistance. On the other hand, it is a risk factor for vitamin D deficiency, thus establishing an inverse relationship between the plasma levels of this nutrient and acute phase proteins with low vitamin D levels, being able to boost the inflammatory response in obesity. In this context, the correction of poor vitamin D status could be an effective addition to the treatment of obesity; however, evidence of future trials that can support the regulatory effects of supplementation is required. The objective of this review is to analyze the existing evidence and establish the relationship between plasma levels of vitamin D and chronic inflammation associated with obesity. The methodology consists of a sensitive search in the PubMed and Trip Database, limiting the search to articles in English and Spanish published through January 2019. Priority was given to clinical trials, original articles and systematic reviews, from which other relevant research was identified.

Keywords: Adipocytokines; Adipose tissue; Calcitriol; Chronic inflammation; Obesity; Vitamin D

RESUMEN

La obesidad se caracteriza por la producción anormal de adipocitocinas, generando inflamación crónica asociada a su vez a disfunción endotelial, aterosclerosis y resistencia a insulina. Por otra parte, es un factor de riesgo de déficit de vitamina D, estableciéndose una relación inversa entre los niveles plasmáticos de dicho nutriente y proteínas de fase aguda, pudiendo potenciar la respuesta inflamatoria en obesidad. En este contexto la corrección del mal estado de vitamina D podría ser una adición efectiva al tratamiento de la obesidad, sin embargo se requiere evidencia de futuros ensayos que se puedan respaldar los efectos reguladores de la suplementación. El objetivo de esta revisión es analizar la evidencia existente y establecer la relación entre los niveles plasmáticos de vitamina D y la inflamación crónica asociada con la obesidad. La metodología consiste en una búsqueda sensible en las bases de datos PubMed y Trip Database, limitándose la búsqueda a artículos en inglés y español hasta enero 2019. Se priorizó por ensayos clínicos, artículos originales y revisiones sistemáticas, a partir de los cuales se identificaron otras investigaciones relevantes.

Palabras clave: Adipocitocinas; Calcitriol; Inflamación crónica; Obesidad; Tejido adiposo; Vitamina D

INTRODUCTION

Obesity has become a serious global health problem due to its close relationship with chronic diseases such as type II diabetes mellitus, hypertension and dyslipidemia, which originates from the imbalance between food intake and energy expenditure1. The accelerated increase in the prevalence of excess weight is essentially due to environmental factors associated with high energy intake, the consumption of food with higher content of saturated fats and simple sugars, together with the decrease in physical activity in all age groups. This generates a process of chronic inflammation that is associated with both insulin resistance (IR) and endothelial dysfunction, which is interrelated with metabolic changes involved in obesity2. These processes alter vascular function, especially considering that endothelial dysfunction is a critical component in the development of atherosclerosis3. In addition, obesity is a risk factor for vitamin D deficiency. An inverse association between concentrations of this nutrient and levels of body fat has been shown, which could be explained by the large storage capacity of adipose tissue.

This fat-soluble vitamin may reduce its bioavailability. Serum vitamin D levels correlate inversely with excess weight and are associated with metabolic syndrome, glucose intolerance4 and body mass index (BMI). Thus, vitamin D, may be a possible modulator of inflammatory response. The objective of this review is to analyze the existing evidence and establish the relationship between plasma levels of vitamin D and chronic inflammation associated with obesity.

REVIEW METHODOLOGY

The present work corresponds to a narrative review, based on a detailed PubMed and Trip Medical Databases search. The search was limited to articles in English and Spanish published through January 2019. Clinical trials, original articles and systematic reviews were prioritized. It should be noted that the selected articles were also used to identify other relevant publications.

Obesity and chronic inflammation

Obesity is considered a serious health problem worldwide5, reaching epidemic proportions and becoming a pathology of high morbidity and mortality6. According to data provided by the World Health Organization (WHO, 2013), there are more than 1,400 million overweight adults in the world, of which 500 million are obese. These rates of excess weight are essentially due to environmental factors associated with food industrialization and high rates of sedentary lifestyle, generating a serious deregulation at the organic level, characterized by the abnormal production of adipocytokines, the presence of oxidative stress and chronic inflammatory response, contributing to the development of morbid events, such as diabetes mellitus type II, hypertension and dyslipidemia. Adipose tissue is composed mainly of adipocytes, which not only store energy in the form of triglycerides, but also act as an active endocrine organ, secretor of several anti-inflammatory and proinflammatory molecules.

Adipose tissue is one of the most abundant tissues of the human body and represents approximately 10% to 60% of total body weight according to the nutritional status of the individual7. This tissue expands through hypertrophy mechanisms, increasing the size of the adipocytes, which enhances the expression and secretion of proinflammatory cytokines that lead to the phosphorylation of the serine 1 substrate of the insulin receptor (IRS-1) through the nuclear factor kappa β (NFkβ), causing IR8. Also, hyperplasia occurs with an increase in the number of adipocytes9, which is triggered by genetic and environmental mechanisms, interfering in the immune regulation of tissues10. Obesity is the main component of the chronic inflammatory state.

This process generates a biological defense response, causing a 2 to 3 times elevation of adipocytokines at a systemic level compared to subjects with normal nutritional status2. As the body weight increases and as a consequence the adipose tissue increases, the blood supply is exceeded, generating an interaction of necrotic adipocytes with macrophages attracted from the bone marrow, due to the monocyte chemoattractant protein I (MCP1), whose inhibition reduces infiltration and slightly improves IR11. Chronic inflammation is associated with both IR and endothelial dysfunction and is interrelated with all metabolic processes involved in obesity that are highly detrimental to vascular function and the health of people1, since endothelial dysfunction is a critical component in the development of atherosclerosis3.

Vitamin D metabolism

Vitamin D is a fat-soluble micronutrient, also called calciferol or antirachitic, which corresponds to an unsaponifiable heterolipide of the group of steroids. There are two forms of vitamin D, the first corresponding to D2 or ergocalciferol that is obtained by irradiation of plants12 and the second is D3 or colecalciferol that is obtained exogenously from the dietary intake of fatty fish or endogenously from its synthesis by exposure to ultraviolet rays at a wavelength of 290 to 315 nm13. Provitamin D3, called 7 dehydrocholesterol, undergoes different conjugations and isomerizations transforming itself into vitamin D3, which will later tie to vitamin D Binding Protein or transcalciferin, which will allow its transport to the liver to undergo the first hydroxylation, catalyzed reaction by hepatic 25 hydroxylase, becoming 25 hydroxyvitamin D3 or calcidiol [25OHD3], which in turn will undergo a second hydroxylation, this time at the renal level by 25(OH)D3 1α hydroxylase, to become 1.25(OH2) D3 or calcitriol14, which will ultimately exert the biological effects, thanks to its action on vitamin D receptor (VDR), which is expressed in most tissues and types of human cells15, giving pleiotropic characteristics to 1.25(OH2)D316.

Vitamin D regulates approximately 3% of human genes through its endocrine effects17. Its binding to the receptor forms a heterodimer with retinoid receptors, joining DNA sequences, for subsequent transcription and translation processes, giving rise to the expression of different genes, such as forming calcium binding proteins, which will increase the absorption of this from intestine to systemic circulation18. For this reason, the production of vitamin D3 will be conditioned to the concentrations of parathyroid hormone and calcium, stimulating and decreasing respectively their serum levels.

Relationship between vitamin D and chronic inflammation associated with obesity

Vitamin D has a recognized role in calcium homeostasis and bone maintenance. According to the the Institute of Medicine, the optimal concentration is 20 ng/ml19. Deficiency causes a decrease in the intestinal absorption efficiency of calcium ingested from food, resulting in secondary hyperparathyroidism and accelerated bone turnover, which can lead to osteoporosis or osteomalacia12, as well as a decrease in the absorption of intestinal phosphorus, since 1,25(OH2)D3 together with parathormone, stimulate the production of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that allows homeostasis of phosphorus20. In addition, it has been shown that there is an inverse association between levels of vitamin D and body fat 21. Recent studies show that hypovitaminosis D is observed in adolescents and obese adults in 90% and 79.4% of cases respectively, associated with high levels of C reactive protein (CRP), total cholesterol and LDL cholesterol22, which has been confirmed by subsequent research in which vitamin D tends to be inversely related to body fat percentage and waist/height ratio23. This can be explained by lower dietary intake, due to the selection of food sources in patients with obesity; reduced cutaneous synthetic capacity24; passive processes associated with the sequestration of this nutrient given excessive hyperplasia of adipocytes. Since vitamin D is fat-soluble; which generates a lower bioavailability25; altered metabolism since recent research indicates that obesity is characterized by a decrease in the expression of 25-hydroxylase CYP2J2 and 1α-hydroxylase CYP27B1 in subcutaneous adipose tissue, while weight loss is associated with an increase in CYP24A1 expression. Adipose tissue has the ability to metabolize vitamin D locally, however, this can be altered with obesity26. Decreased hydroxylation, given by the low concentrations observed in obese subjects of enzymes that catalyze the conversion to active vitamin, decrease the formation of active metabolites in obese individuals27, which is correlated with comorbidities such as hypertension and diabetes mellitus, markers of subclinical atherosclerosis, and, cardiovascular events such as acute myocardial infarction and cerebrovascular accident. Thus, vitamin D may be able to act as a possible immune modulator, interfering with the chronic inflammatory response4 since it has been observed to exert protective effects on the vasculature28, with calcitriol levels <60 pmol/L reported as a cardiovascular risk factor29.

In this context, serum levels of vitamin D have been found to be inversely proportional to concentrations of proinflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin 6 (IL6) in obese subjects4 Vitamin D may even prevent the destruction of pancreatic β cells and reduce the incidence of autoimmune diabetes, possibly secondary to the inhibition of the aforementioned cytokines30. On the other hand, vitamin D negatively controls the activation of NFKβ, an important gene regulator that codes for the generation of inflammatory cytokines and influences IR mechanisms31 Specifically, an inverse relationship between 25(OH)D levels and acute phase proteins is established32 and increases in IR4.

Supplementation for 12 months with 83.3 ug/day (3332 IU) of vitamin D induces a decrease in circulating levels of TNFα29. However, treatment with 100,000 IU of this vitamin during a period of 3 months had no effect on the endothelial function of obese adolescents with plasma levels lower than 75 nmol/L, despite having increased the levels of 25(OH)D33. This result is likely associated with the duration of the study, since other long-duration research has shown the positive impact of vitamin D treatment, guaranteeing endothelial stabilization in an obese population34. On the other hand, supplementation with 50 ug of vitamin D for 9 months increased the plasma concentrations of anti-inflammatory cytokine interleukin 10 (IL10) and prevented the increase of TNFα in subjects with coronary disease, associated with systemic inflammation35. In data provided by Carrillo et al, supplementation with 4000 IU/day of vitamin D in active subjects did not influence the levels of inflammatory biomarkers36. On the other hand, polymorphisms in VDR genes are associated with insulin resistance and high glucose concentrations37, highlighting that vitamin D has a possible stimulatory role in the expression of insulin receptors and its low plasma level could potentiate the inflammatory response in obese subjects. Some studies have shown inverse associations between circulating concentrations of 25(OH)D and elevated fasting glucose and insulin, while others have established a similar inverse relationship to pancreatic β cell function and a positive association with insulin sensitivity38. In conclusion it is suggested that the state of hypovitaminosis D is inversely related to the parameters of obesity17, which is why correcting the poor state of vitamin D through dietary supplementation may be an effective addition to the standard treatment of obesity and its insulin-associated resistance23-39, however, evidence of future clinical trials is required to support the potential regulatory effects of vitamin D supplementation in order to reduce obesity levels.

REFERENCES

1. Heber D. An integrative view of obesity. Am J Clin Nutr. 2010; 91 (Dk 07688): 280-283. [ Links ]

2. Lowe G, Woodward M, Hillis G, et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the advance study. Diabetes 2014; 63(3): 1115-1123. [ Links ]

3. Deng G, Long Y, Yu Y-R, Li M-R. Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK-eNOS Pathway. Int J Obes (Lond) 2010; 34(1): 165-171. [ Links ]

4. Bellia A, Garcovich C, D'Adamo M, et al. Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Intern Emerg Med 2011; 8(1): 33-40. [ Links ]

5. Tsai A, Williamson D, dick H. Direct medical cost of overweight and obesity in the United States: a quantitative systematic review. Int Assoc Study Obes 2011; 12(1): 50-61. [ Links ]

6. Weigl J, Holzapfel C. Der Body-Mass-Index macht headline: When is the mortality rate lowest? Dtsch Med Wochenschr. 2016; 141(14): 1040-1041. [ Links ]

7. Baudrand R., Eugenio AU, Manuel MG. Fat tissue as an endocrine modulator: Hormonal changes associated with obesity. Rev Med Chil 2010; 138(10): 1294-1301. [ Links ]

8. Giordano A, Murano I, Mondini E, et al. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res 2013; 54(9): 2423-2436. [ Links ]

9. Siriwardhana N, Kalupahana NS, Cekanova M, LeMieux M, Greer B, Moustaid-Moussa N. Modulation of adipose tissue inflammation by bioactive food compounds. J Nutr Biochem 2013; 24(4): 613-623. [ Links ]

10. Erikci Ertunc M, Hotamisligil GS. Lipid signaling and lipotoxicity in metabolic inflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 2016: 1-56. [ Links ]

11. Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116(6): 1494-1505. [ Links ]

12. Holick MF. Vitamin D status: Measurement, interpretation and clinical application. Ann Epidemiol. 2009;19(2):73-78. [ Links ]

13. Holick MF. Resurrection of vitamin D and rickets. J Clin Invest 2006; 116(8): 2062-2072. [ Links ]

14. Mendoza-Zubieta V, Reza-Albarrán A. Vitamin D, obesity and insulin resistance: A triangle not so loving. Rev Endocrinol y Nutr 2011; 19(4): 136-139. [ Links ]

15. Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 2005; 26(5): 662-687. [ Links ]

16. Chauhan B. Role of Vitamin D Receptor (Vdr) Gene Polymorphism. World J Pharm Pharm Sci. 2017; 6(7): 1083-1095. [ Links ]

17. Jamka M, Wožniewicz M, Walkowiak J, Bogdański P, Jeszka J, Stelmach-Mardas M. The effect of vitamin D supplementation on selected inflammatory biomarkers in obese and overweight subjects: a systematic review with meta-analysis. Eur J Nutr. 2015; 55(6): 2163-2176. [ Links ]

18. Chatterjee M. Vitamin D and genomic stability. Mutat Res Mol Mech Mutagen. 2001; 475(1): 69-87. [ Links ]

19. Ross AC, Manson JE, Abrams SA, et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know. J Clin Endocrinol Metab 2011; 96(1): 53-58. [ Links ]

20. Stremke ER and Hill Gallant KM. Intestinal phosphorus absorption in chronic kidney disease. Nutrients 2018; 10(10):2-11. [ Links ]

21. Soares MJ, Pathak K, Calton EK. Calcium and vitamin D in the regulation of energy balance: Where do we stand? Int J Mol Sci 2014; 15(3): 4938-4945. [ Links ]

22. Teixeira J, Ferreira A, et al. Vitamin D nutritional status and its relationship with metabolic changes in adolescents and adults with severe obesity. Nutr Hosp 2018; 35(4): 847-853. [ Links ]

23. Pantovic A, Zec M, Zekovic M, Obrenovic R, Stankovic S and Glibetic M. Vitamin D Is Inversely Related to Obesity: Cross-Sectional Study in a Small Cohort of Serbian Adults. J Am Coll Nutr 2019; Jan(11): 1-10. [ Links ]

24. Hamid Mehmood ZTN, Papandreou D. An updated mini review of Vitamin D and obesity: Adipogenesis and inflammation state. Maced J Med Sci 2016; 4(3): 526-532. [ Links ]

25. Chrysostomou S and Saranti E. The Effect of Vitamin D Supplementation on the Treatment of Overweight and Obesity: A Systematic Review of Randomized Controlled Trials. J Obes Ther. 2017; 1(2). [ Links ]

26. Wamberg L et al. Expression of vitamin D-metabolizing enzymes in human adipose tissue the effect of obesity and diet-induced weight loss. Int J Obes (Lond) 2013; 37(5): 651-657. [ Links ]

27. Rafiq S, Jeppesen PB. Body Mass Index, Vitamin D, and Type 2 Diabetes: A Systematic Review and Meta-Analysis. Nutrients 2018; 10(9). [ Links ]

28. Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: A systematic review. Nat Rev Cardiol. 2009; 6(10): 621-630. [ Links ]

29. Zittermann A, Frisch S, Berthold HK, et al. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr 2009; 89(5): 1321-1327. [ Links ]

30. Zittermann A, Gummert JF. Nonclassical vitamin D Actions. Nutrients 2010; 2(4): 408-425. [ Links ]

31. D'Ambrosio D, Cippitelli M, Cocciolo MG, et al. Inhibition of IL-12 production by 1, 25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 1998; 101(1): 252-262. [ Links ]

32. Munger KL, Levin LI, Holls BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. Jama 2006; 296(23): 2832-2838. [ Links ]

33. Javed A, Kullo IJ, Balagopal PB, Kumar S. Effect of vitamin D3 treatment on endothelial function in obese adolescents. Pediatr Obes 2016; 11(4): 279-284. [ Links ]

34. Piccolo BD, Dolnikowski G, Seyoum E, et al. Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults. Nutrients 2013;5(9): 3352-3366. [ Links ]

35. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006; 86(4): 754-759. [ Links ]

36. Carrillo-Vega MF, García-Peña C, Gutiérrez-Robledo LM, Pérez-Zepeda MU. Vitamin D deficiency in older adults and its associated factors: a cross-sectional analysis of the Mexican Health and Aging Study. Arch Osteoporos 2017; 12(1): 8. [ Links ]

37. Chiu KC, Chuang LM, Yoon C. The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians. BMC Med Genet 2001; 2: 2. [ Links ]

38. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and Beta cell dysfunction. Am J Clin Nutr 2004; 25(4): 820-825. [ Links ]

39. Belenchia Anthony M, Peterson AKTLSHCA. Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr 2013; 20(7): 817-823. [ Links ]

Received: October 15, 2018; Revised: January 08, 2019; Accepted: March 22, 2019

*Dirigir correspondencia a: Carla Guzmán. Carrera Nutrición y Dietética, Facultad Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Concepción, Chile. Programa Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco, Chile. Lientur 1457, Concepción 4080871, Chile. Teléfono: +56 41 248 7289 E-mail: carla.guzman@uss.cl

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