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The effect of four-week levothyroxine treatment on hormonal regulation of adenylyl cyclase in the brain and peripheral tissues of obese rats

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Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

The decrease in the function of thyroid gland (TG), which is often observed in obesity and metabolic syndrome, results in the hypothyroid state and is one of the causes of metabolic and functional disorders. It is assumed that thyroid hormone treatment normalizing hormone levels in an organism is able to prevent these disorders. However, studies of the effect of this therapy on metabolic parameters in animals with experimental obesity are very scarce, and data concerning its influence on the activity of the adenylyl cyclase signaling system (ACSS) are absent. At the same time, it is known that disturbances in the hormonal regulation of ACSS play a key role in etiology and pathogenesis of diseases associated with metabolic disorders. This work was aimed at studying the effect of long-term levothyroxine treatment of obese male rats on their carbohydrate and lipid metabolism, thyroid status, and the activity of ACSS and its hormonal regulation in the brain, myocardium, epididymal fat, and TG. The rats with obesity caused by a three-month high-fat diet received levothyroxine for four weeks (orally, with a daily dose of 20 μg/kg) (group OB + LT), whereas the control animals and untreated obese rats received placebo instead of the hormone. As a result of the treatment, the levels of thyroid hormones increased, the body and adipose tissue weight decreased, the levels of triglycerides, total and atherogenic cholesterol decreased, and glucose utilization increased. In addition, the ACSS activity impaired in obesity was restored in the brain, myocardium, and epididymal fat tissue. In the brain, the levothyroxine treatment restored the stimulatory effects of serotonin and dopamine, as well as the inhibitory effects of the agonists of the subtype 1B 5-hydroxytryptamine receptor and type-2 dopamine receptor on the adenylyl cyclase (AC) activity. In the myocardium, the stimulatory effects of β1/β2-agonists and relaxin reduced in obesity were also restored. It should be noted, however, that the effects of β3-agonists augmented in obesity did not change in group OB + LT, resulting in the enhanced activating influence of β-agonists on AC and creating certain risks of the development of cardiovascular diseases. The increase in the lipolytic effect of β-agonists and the weakening of the antilipolytic effect of N6-cyclopentyladenosine, an agonist of type 1 adenosine receptor, was found in the epididymal fat, indicating the increased lipolysis in adipose tissue. The sensitivity of AC to the thyroid-stimulating hormone in TG decreased in group OB + LT with an excess of thyroid hormones. Thus, the treatment with levothyroxine not only improves the energy metabolism and prevents the deficiency of thyroid hormones in experimental obesity but also restores the hormonal regulation of ACSS, which can be one of the mechanisms of action of thyroid hormones on the brain and peripheral tissue functions in obesity and other metabolic disorders associated with the hypothyroid state.

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Abbreviations

AR:

adrenergic receptor

AC:

adenylyl cyclase

ACSS:

adenylyl cyclase signaling system

DAR:

dopamine receptor

M4R:

type 4 melanocortin receptor

MS:

metabolic syndrome

MSH:

melanocyte-stimulating hormone

5-NOT:

5-nonyloxy-tryptamine

5-HTR:

5-hydroxytryptamine (serotonin) receptor

C-HDLP and C-LDLP:

high and low density lipoprotein-bound cholesterol, respectively

TG:

thyroid gland

BRL-37344:

[4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]acetic acid sodium salt

CL-316243:

[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxol-2,2-dicarboxylic acid diso-dium salt

GppNHp:

5'-Guanylyl imidodiphosphate

Gs and Gi proteins:

stimulatory and inhibitory heterotrimeric G proteins, respectively

HOMA-IR:

homeostasis model assessment of insulin resistance

8-OH-DPAT:

8-hydroxy-2-(di-n-propylamino)tetraline

PACAP-38:

pituitary adenylyl cyclase-activating polypeptide-38

T3 :

triiodothyronine

T4 :

thyroxin

THIQ:

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)-1-piperidinyl]-2-oxoethyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences, pr. M. Thoreza 44, St. Petersburg, 194223, Russia

    K. V. Derkach, L. A. Kuznetsova, O. V. Chistyakova, P. A. Ignatieva & A. O. Shpakov

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  1. K. V. Derkach
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  2. L. A. Kuznetsova
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  3. O. V. Chistyakova
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  4. P. A. Ignatieva
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  5. A. O. Shpakov
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Correspondence to A. O. Shpakov.

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Original Russian Text © K.V. Derkach, L.A. Kuznetsova, O.V. Chistyakova, P.A. Ignatieva, A.O. Shpakov, 2015, published in Biologicheskie Membrany, 2015, Vol. 32, No. 4, pp. 253–264.

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Derkach, K.V., Kuznetsova, L.A., Chistyakova, O.V. et al. The effect of four-week levothyroxine treatment on hormonal regulation of adenylyl cyclase in the brain and peripheral tissues of obese rats. Biochem. Moscow Suppl. Ser. A 9, 236–245 (2015). https://doi.org/10.1134/S1990747815040030

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