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ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus-pituitary-thyroid axis in male mice.

ABSTRACT: Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1^-/-) model. The results show that Adgra1^-/- male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and β3-adrenergic receptor (β3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus-pituitary-thyroid axis. Finally, Adgra1^-/- male mice present abnormal activation of PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1^-/- female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus-pituitary-thyroid axis by regulating PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.

SUBMITTER: Zhang XH

PROVIDER: S-EPMC8024368 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neonatal stress contributes to the development of obesity and has long-lasting effects on elements of the hypothalamus-pituitary-thyroid (HPT) axis. Given the importance of thyroid hormones in metabolic regulation, we studied the effects of maternal separation and a high-fat/high-carbohydrate diet (HFC), offered from puberty or adulthood, on HPT axis activity of adult male and female Wistar rats. Pups were non-handled (NH) or maternally separated (MS) 3 h/day at postnatal days (Pd) 2-21. In a first experiment, at Pd60, rats had access to chow or an HFC diet (cookies, peanuts, chow) for 1 month. Male and female NH and MS rats that consumed the HFC diet increased their caloric intake, body weight, and serum insulin levels; fat weight increased in all groups except in MS males, and serum leptin concentration increased only in females. Mediobasal hypothalamus (MBH) Pomc expression increased in NH-HFC females and Npy decreased in NH-HFC males. MS males showed insulinemia and hypercortisolemia that was attenuated by the HFC diet. The HPT axis activity response to an HFC diet was sex-specific; expression of MBH thyrotropin-releasing hormone-degrading ectoenzyme (Trhde) increased in NH and MS males; serum TSH concentration decreased in NH males, and T4 increased in NH females. In a second experiment, rats were fed chow or an HFC diet from Pd30 or 60 until Pd160 and exposed to 1 h restraint before sacrifice. Regardless of neonatal stress, age of diet exposition, or sex, the HFC diet increased body and fat weight and serum leptin concentration; it induced insulinemia in males, but in females only in Pd30 rats. The HFC diet's capacity to curtail the hypothalamus-pituitary-adrenal axis response to restraint was impaired in MS males. In restrained rats, expression of Trh in the paraventricular nucleus of the hypothalamus, Dio2 and Trhde in MBH, and serum thyroid hormone concentration were altered differently depending on sex, age of diet exposition, and neonatal stress. In conclusion, metabolic alterations associated to an HFC-diet-induced obesity are affected by sex or time of exposition, while various parameters of the HPT axis activity are additionally altered by MS, pointing to the complex interplay that these developmental influences exert on HPT axis activity in adult rats.

Project description:IntroductionThe vestibular acute stress induces reversible alert-like reactions that involve the sympathetic adrenal-medullar system and hypothalamic-pituitary-adrenal axis responses. The present study aimed to evaluate salivary α-amylase and salivary cortisol production in relation with cardiovascular reactivity induced by acute stress in healthy subjects.Material and methodsForty-eight young healthy male volunteers were examined under basal conditions and at various times after reaching the maximal nystagmic reaction following air caloric vestibular test. Heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure were recorded at the same time as measurement of the salivary α-amylase and salivary cortisol. At the end of the caloric vestibular test session, perceived stress scale questionnaires were administered to measure the self-perceived stress impact induced by the task, and individual scores were compared with those measured on the enrollment day.ResultsFollowing caloric vestibular test-evoked vertigo, salivary α-amylase and cortisol showed distinct trends in their production after acute stress: Student's t-test was used to compare the α-amylase vs cortisol slopes of the respective interpolated regression lines, and the difference was significant (t = -3.283; p<0.001); an increase in salivary cortisol production corresponded with a decrease in the salivary α-amylase concentration. In addition, salivary biomarker modifications were associated with consistent changes in the heart rate, systolic blood pressure and mean arterial pressure.ConclusionsUsing the air caloric vestibular test task as a stressor, the present study demonstrated a connection between the acute hormonal stress response to vestibular stimulation and cardiovascular output. However, further research is needed before we can define the potential importance of the consistent cardiovascular activity changes evoked by vestibular stimulation and the possible functional consequences for cardiovascular regulation and orthostatic tolerance in humans.

Project description:Background and purposeThis study sought to improve methods to identify biomarkers in the neuroendocrine system related to stroke progression to improve the accuracy of traditional tools for evaluating stroke prognosis.MethodsSeventy-four stroke patients and 237 healthy controls were prospectively included. We measured urinary epinephrine (E), noradrenaline (NE), dopamine (DA) and cortisol (F) on days 1, 3, and 5 after stroke onset and plasma F, adrenocorticotropic hormone (ACTH), thyrotropin (TSH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and growth hormone (GH). The correlation between these hormone levels and 90-day prognosis was analyzed, their value in assessing prognosis was compared with lesion volume and National Institutes of Health Stroke Scale (NIHSS) scores using receiver operating characteristic (ROC) curves, and their correlation with conventional clinical variables was assessed.ResultsLevels of F, 24-h urinary free cortisol(UFC), E, NE, DA, and GH on days 1, 3, and 5 were significantly higher in stroke patients than in controls (P < 0.01), while ACTH and TSH decreased, gradually approaching normal within 5 days of onset. Levels of E, NE, F, and 24-h UFC were proportional to severity, and all gradually decreased within 5 days of onset in patients with a good prognosis and gradually increased or remained high in those with a poor prognosis. After adjustment for age, sex, NIHSS, or Glasgow Coma Scale (GCS) score, F > 13.6 μg/dL, ACTH > 22.02 pg/mL and NE > 123.5 μg/ 24 h were identified as risk factors for a poor prognosis 90 days after stroke (P < 0.05). The combination of F, ACTH, NE, white blood cell count (WBC), glucose (Glu), and hemoglobin (Hb) was significantly more accurate than lesion volume (AUC: 0.931 vs. 0.694 P = 0.019) and NIHSS score (AUC: 0.931 vs. 0.746 P = 0.034) in predicting poor prognosis of stroke 1 day after onset. Hormones and traditional clinical variables were correlated to varying degrees, with NE correlating most strongly with 24-h UFC (r = 0.54) and moderately positively with lesion volume (r = 0.40) and NIHSS score (r = 0.45).ConclusionsStroke causes significant time-phased dynamic changes in the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, and plasma F, ACTH, and urinary NE levels can be used to assess stroke severity and prognosis.Chinese clinical trial registryRegistration Number: ChiCTR1900024992. Registration Date: 2019/8/6.

Project description:IntroductionProlonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T3 availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3 syndrome in prolonged critical illness.MethodsHealthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors alpha (TRalpha) and beta (TRbeta) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes.ResultsIn the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T4) and low-normal T3 concentrations, without a change at the thyroid hormone receptor level.ConclusionsAlthough expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T4 and T3 content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role.

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ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus-pituitary-thyroid axis in male mice.

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