Open Access

Carbimazole inhibits TNF-α expression in Fat-induced hypothyroidism

Journal of Diabetes & Metabolic Disorders201413:83

DOI: 10.1186/s40200-014-0083-4

Received: 21 October 2013

Accepted: 22 July 2014

Published: 21 August 2014

Abstract

The effect of the carbimazole on expression of tumor necrosis factor (TNF-α) in liver, was investigated in an experimental model of high fat diet (HFD) induced obesity. The HFD (orally given for 4 months) induced TNF-α in liver tissue along with raised serum triglyceride (TG), cholesterol and high TSH (62%). In carbimazole (1 mg/100 gbw) treatment, the induction of TNF-α was significantly inhibited, without affecting other parameters. It also improved the liver function, which was raised due to HFD in experimental control rats.

Keywords

Obesity High fat diet Carbimazole TNF-α

Introduction

The inflammation is the primary cause of metabolic syndrome [MS] [1]. It is associated with faulty life style and food habits [2] and results to ectopic fat deposition [3]. The involvement of adipogenesis and high TSH has been reported [4],[5]. The raised inflamation is due to accumulation of M-1 macrophages [6]. Whether this induction is a cause or effect of obesity is debatable. Similar to pre-diabetic patient with impaired glucose tolerance (IGT), where both insulin and glucose levels are higher, [7],[8] raised TSH may be adaptive as reported by others also [9]. Here we have investigated role of Carbimazole on high fat diet induced expression of inflammatory markers and tried to correlate the inter relationship between obesity, thyroid function and inflammation.

Material and methods

The rats were divided into group-1 (maintained normal diet and water). Group –2 [received high fat diet (HFD) (lard [400 g/lit], 20% fructose, casein [80 g/lit], cholesterol] Group- 3 [received HFD + Carbimazole (Abbott, HP, India) (1 mg/100 gbw)]. Above treatments were continued for 4 months and finally rats were sacrificed to assess lipid profile (serum triglyceride (TG) and cholesterol) and liver function test namely aminotransferase (AST), Alanine transaminase (ALT), and alkaline phosphatase (ALKP) and thyroid stimulating hormone (TSH). The expression of TNF-alpha was determined in Liver tissue by RT-PCR [10].

Ethical clearance: The protocol was approved by animal ethics committee of our Institution (IMS, BHU-letter # Dean/2005-06/Animal Ethical Committee/390 dated-18.05.2006).

Results

Lipid profile, liver function and TSH were significantly raised in animals fed with HFD (Table 1). There was high expression of TNF-α (Figure 1) also in these rats. In Carbimazole treated animals (group 2) there was significant prevention in rise of liver function enzymes and TNF-α, without significant change in serum TG, cholesterol and TSH.
Table 1

Blood biochemistry after 4 months of various treatments

Diet type

Normal

HFD (experimental control)

HFD + Carbimazole

Body weight [g]

165 ± 7.0

162.5 ± 37.5

167 ± 22.1

Triglycerides [mg/dl]

85.8 ± 9.3

115.6 ± 33

124 ± 45

Cholesterol [mg/dl]

72.5 ± 10.2

110 ± 45

96.9 ± 13.6

AST [U/L]

72.5 ± 10.2

126.6 ± 9.9

113.1 ± 12.3*

ALT [U/L]

72.2 ± 10.2

105.9 ± 3.2

92.9 ± 5.73*

ALP [U/L]

441.8 ± 8.2

361.2 ± 30.8

373.5 ± 18.8

TSH [µU/ml]

0.3 ± 0.024

0.8 ± .040

0.7 ± .032

Data presented as mean ± SD. P value: (N = 6), *< 0.05 when compared experimental control with carbimazole treated rat.

Figure 1

RT-PCR assessment of TNF-α [4 months] photograph normalized with GAPDH. A: rats with high fat diet (HFD) B: Rats with HFD + Carbimazole, C: normal rats, D: 200 bp DNA ladder.

Discussion

It is well documented that faulty diet and life style mediated physiological changes induces systemic low grade inflammation [LGI]. Our results indicate the raised serum TSH and TNF-α in high fat diet fed rats and lower in carbimazole treated rats (when compared to normal control animals of Gr-1). This could be due to inhibitory action of carbimazole on Rac1, involved in expression of TNF-α [11]. Since, TSH level remains same as in experimental control (only HFD rats), there could direct inhibitory effect of TSH on expression of TNF-α as reported earlier in case of osteoclast [12]. High release of Leptin by adipocytes is reported in obesity, which further induces TSH [9]. Accumulation of triglycerides in Gr 2 and Gr3 animals could an adaptive mechanism to reduce circulating free fatty acid, as it is involved in insulin resistance and systemic inflammation. Thus it could be considered as protective mechanism. The raised TSH in obesity further enhances the release of T3 and T4, responsible for rise in thermogenesis and reduction of deposited lipid [13]. Thus low T3 and T4 in established obesity could be an indication of failure of system in counteracting the obesity. Many reports suggest that hypothyroidism could be the cause for obesity. Diez et al. have reported TNF –α mediated destruction of thyroid cells, resulting to low T3/T4 and raised TSH [14]. It is associated with accumulation of adipose-tissue-embedded macrophages in obesity. Higher Leptin in obese, is another factor to increase TSH. Contrary to this, raised TSH inhibits secretion of TNF–α in some cells like osteoclast [12]. This may happen in other tissue also where TSH receptor are reported. Thus, hypothyroid condition in obesity could be an initial step to regulate the abnormal physiology, but it needs further experimental evidences.

Conclusion

The inhibition of TNF –α expression in carbimazole treated group could be its direct anti-inflammatory effect, but it can also be through high TSH, which needs further exploration.

Declarations

Authors’ Affiliations

(1)
Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University

References

  1. Paschos P, Paletas K: Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia 2009, 13: 9–19.PubMedPubMed CentralGoogle Scholar
  2. Dullo AG, Montani JP: Body composition, inflammation and thermogenesis in pathways to obesity and the metabolic syndrome: an overview. Obes Rev 2012, 13: 1–5. 10.1111/j.1467-789X.2012.01032.xView ArticleGoogle Scholar
  3. Mathieu P, Lemieux I, Després JP: Obesity, inflammation, and cardiovascular risk. Clin Pharmacol Therapeut 2010, 87: 4.
  4. Dietlein M, Kahaly G, Kobe C, Schmidt M, Derwahl KM, Schicha H: Obesity, energy regulation and thyroid function: is borderline elevated TSH-level the cause or secondary phenomenon of obesity. Nuklearmedizin 2008, 47: 181–187.PubMedGoogle Scholar
  5. Qatanani M, Lazar MA: Mechanisms of obesity-associated insulin resistance: many choices. Genes Dev 2007, 21: 1443–1455. 10.1101/gad.1550907View ArticlePubMedGoogle Scholar
  6. Heilbronn LK, Campbell LV: Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 2008, 14: 1225–1230. 10.2174/138161208784246153View ArticlePubMedGoogle Scholar
  7. Beaudry JL, Riddell MC: Effects of glucocorticoids and exercise on pancreatic β-cell function and diabetes development. Diabetes Metab Res Rev 2012, 28: 560–573. 10.1002/dmrr.2310View ArticlePubMedGoogle Scholar
  8. Mykkanen L, Haffner SM, Kuusisto J, Pyorala K, Hales CN, Laakso M: Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects. Diabetologia 1995, 38: 1176–1182. 10.1007/BF00422366View ArticlePubMedGoogle Scholar
  9. Verma A, Jayaraman M, Kumar HK, Modi KD: Hypothyroidism and obesity. Cause or effect? Saudi Med J 2008, 29: 1135–1138.PubMedGoogle Scholar
  10. Lin RK, Zhang CH, Mu N, Yao QY, Dong SL, Ai QB, Wang QX: Effects of astilbin on the expression of TNF alpha and IL-10 in liver warm ischemia-reperfusion injury. Zhonghua Gan Zang Bing Za Zhi 2010, 18: 463–466.PubMedGoogle Scholar
  11. Humar M, Dohrmann H, Stein P, Andriopoulos N, Goebel U, Roesslein M, Schmidt R, Schwer CI, Loop T, Geiger KK, Pahl HL, Pannen BH: Thionamides inhibit the transcription factor nuclear factor-KB by suppression of Rac1 and inhibitor of Kappa B Kinase-α. J Pharmacol Exp Ther 2007, 324: 3.
  12. Hase H, Ando T, Eldeiry L, Brebene A, Peng Y, Liu L, Amano H, Davies TF, Sun L, Zaidi M, Abe E: TNF alpha mediates the skeletal effects of thyroid-stimulating hormone. Proc Natl Acad Sci U S A 2006, 103: 12849–12854. 10.1073/pnas.0600427103View ArticlePubMedPubMed CentralGoogle Scholar
  13. Biondi B: Thyroid and obesity: an intriguing relationship. J Clin Endocrinol Metab 2010, 95: 3614–3617. 10.1210/jc.2010-1245View ArticlePubMedGoogle Scholar
  14. Diez JJ, Hernanz A, Medina S, Bayon C, Iglesias P: Serum concentrations of tumor necrosis factor-alpha (TNF-α) and soluble TNF-α receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function. Clin Endocrinol (Oxf) 2002, 57: 515–521. 10.1046/j.1365-2265.2002.01629.xView ArticleGoogle Scholar

Copyright

© Tripathi and Pandey; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement