Role of extrathyroidal TSHR expression in adipocyte differentiation and its association with obesity

<p>Abstract</p> <p>Background</p> <p>Obesity is known to be associated with higher risks of cardiovascular disease, metabolic syndrome, and diabetes mellitus. Thyroid-stimulating hormone (TSHR) is the receptor for thyroid-stimulating hormone (TSH, or thyrotropin), the key regulator of thyroid functions. The expression of TSHR, once considered to be limited to thyrocytes, has been so far detected in many extrathyroidal tissues including liver and fat. Previous studies have shown that TSHR expression is upregulated when preadipocytes differentiate into mature adipocytes, suggestive of a possible role of TSHR in adipogenesis. However, it remains unclear whether TSHR expression in adipocytes is implicated in the pathogenesis of obesity.</p> <p>Methods</p> <p>In the present study, TSHR expression in adipose tissues from both mice and human was analyzed, and its association with obesity was evaluated.</p> <p>Results</p> <p>We here showed that TSHR expression was increased at both mRNA and protein levels when 3T3-L1 preadipocytes were induced to differentiate. Knockdown of TSHR blocked the adipocyte differentiation of 3T3-L1 preadipocytes as evaluated by Oil-red-O staining for lipid accumulation and by RT-PCR analyses of PPAR-γ and ALBP mRNA expression. We generated obesity mice (C57/BL6) by high-fat diet feeding and found that the TSHR protein expression in visceral adipose tissues from obesity mice was significantly higher in comparison with the non-obesity control mice (<it>P </it>< 0.05). Finally, the TSHR expression in adipose tissues was determined in 120 patients. The results showed that TSHR expression in subcutaneous adipose tissue is correlated with BMI (body mass index).</p> <p>Conclusion</p> <p>Taken together, these results suggested that TSHR is an important regulator of adipocyte differentiation. Dysregulated expression of TSHR in adipose tissues is associated with obesity, which may involve a mechanism of excess adipogenesis.</p

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients

Objectives. To evaluate the effect of levothyroxine (LT4) replacement therapy on nonalcoholic fatty liver disease (NAFLD) in subclinical hypothyroidism (SCH) patients. Methods. This study was a post hoc analysis of a randomized controlled trial and involved 33 significant and 330 mild SCH patients. All of the significant SCH patients received LT4 supplement. The mild SCH patients were grouped as LT4 treated or not. After 15 months of follow-up, prevalence of NAFLD in each group was reevaluated. Subgroup analysis was conducted in mild SCH patients with dyslipidemia. Results. After treatment with LT4, the prevalence of NAFLD in significant SCH patients reduced from 48.5% to 24.2% (p=0.041). In mild SCH patients, prevalence of NAFLD and serum alanine aminotransferase (ALT) was not significantly affected by LT4 supplementation. Nonetheless, mild SCH patients with dyslipidemia who received LT4 treatment experienced decreases in the prevalence of NAFLD and serum ALT levels (p<0.05 for both). In contrast, these parameters remained comparably stable in patients who were not treated. Conclusion. LT4 supplementation has benefits on NAFLD in significant SCH patients or mild SCH patients with dyslipidemia. For NAFLD patients with SCH, appropriate supplementation of LT4 may be an effective means of controlling NAFLD. The original trial was registered with ClinicalTrials.gov (NCT01848171)

Energy deficiency promotes rhythmic foraging behavior by activating neurons in paraventricular hypothalamic nucleus

BackgroundDysregulation of feeding behavior leads to a variety of pathological manifestations ranging from obesity to anorexia. The foraging behavior of animals affected by food deficiency is not fully understood.MethodsHome-Cage system was used to monitor the behaviors. Immunohistochemical staining was used to monitor the trend of neuronal activity. Chemogenetic approach was used to modify neuronal activity.ResultsWe described here a unique mouse model of foraging behavior and unveiled that food deprivation significantly increases the general activities of mice with a daily rhythmic pattern, particularly foraging behavior. The increased foraging behavior is potentiated by food cues (mouthfeel, odor, size, and shape) and energy deficit, rather than macronutrient protein, carbohydrate, and fat. Notably, energy deficiency increases nocturnal neuronal activity in paraventricular hypothalamic nucleus (PVH), accompanying a similar change in rhythmic foraging behavior. Activating neuronal activity in PVH enhances the amplitude of foraging behavior in mice. Conversely, inactivating neuronal activity in PVH decreases the amplitude of foraging behavior and impairs the rhythm of foraging behavior.DiscussionThese results illustrate that energy status and food cues regulate the rhythmic foraging behavior via PVH neuronal activity. Understanding foraging behavior provides insights into the underlying mechanism of eating-related disorders

High-Level Expression of Notch1 Increased the Risk of Metastasis in T1 Stage Clear Cell Renal Cell Carcinoma

Background: Although metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC. Methodology/Principal Findings: The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1

The effect of LRRK2 loss-of-function variants in humans

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery. Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes(1,2). Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease(3,4), suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns(5-8), the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)(9), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work(10), confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.Peer reviewe

Prevalence, awareness, treatment and control of diabetes mellitus among middle-aged and elderly people in a rural Chinese population: A cross-sectional study.

Diabetes mellitus ranks high on the international health agenda as a global pandemic and as a threat to human health and global economies. A total of 10851 participants aged over 40 years were included in the cross-sectional analysis. This observational study analyzed the prevalence of diabetes mellitus and the awareness, treatment and glycemic control of diabetes in a rural Chinese population. Approximately 25% of middle-aged and elderly rural Chinese residents had diabetes in 2010-2011. The prevalence was higher with older age, dyslipidemia, higher body mass index and larger waist circumference. Among the subjects with diabetes, 40.3% were aware of their condition; 62.9% were receiving treatment, and 16.9% had controlled diabetes. Metformin was the majority oral antidiabetic drug treatment most often prescribed, for either monotherapy or combined therapy. These results indicate that diabetes has become an urgent public health problem in the Chinese rural population because of its high prevalence and low rates of awareness, treatment and control. The management and prevention of diabetes mellitus should be considered an essential strategy at the level of public health

Physical Activity Patterns and Risk of Type 2 Diabetes and Metabolic Syndrome in Middle-Aged and Elderly Northern Chinese Adults

The main aim of this study is to quantitatively describe the status of physical activity and evaluate its levels in a rural population and to investigate the association between the quantifiable physical activity and type 2 diabetes and metabolic syndrome. In total, 2076 participants aged over 40 years were included in a cross-sectional analysis. Physical activity status and the contributions of different types of activity were evaluated. The association between social behaviors and physical activities was analyzed. In addition, the impact of physical activities on type 2 diabetes mellitus and metabolic syndrome was also analyzed by logistic regression. Approximately half of the total activity in rural areas consisted of work-related activity (49.3%) followed by commuting (30.2%) and recreational activity (20.5%). In rural areas, the prevalence of physical activity levels was 28.6% for low levels, 47.3% for moderate levels, and 24.1% for high levels. Educational level showed a significant negative association with the physical activity level. Lower physical activity shows a strong and significant association with type 2 diabetes and metabolic syndrome. In conclusion, insufficient physical activity among rural people over 40 years old increases the risk of type 2 diabetes and metabolic syndrome. Population-wide and individualized guidelines for physical activities especially recreational physical activities should be developed

High Circulating Follicle-Stimulating Hormone Level Is a Potential Risk Factor for Renal Dysfunction in Post-Menopausal Women

ObjectiveMenopause contributes to renal dysfunction in women, which is generally attributed to estrogen withdrawal. In addition to decreased estrogen level, serum follicle-stimulating hormone (FSH) level increases after menopause. This study investigated the association between high circulating FSH level and renal function in post-menopausal women.MethodsThis observational cross-sectional study included 624 pre-menopausal, 121 peri-menopausal, and 2540 post-menopausal women. The levels of female sex hormones were examined by chemiluminescence and indices of renal function were measured using a clinical chemistry analyzer. The post-menopausal women were grouped into quartiles according to serum FSH levels.ResultsRenal function progressively declined from pre-menopause to peri-menopause to post-menopause, which was accompanied by increasing serum FSH level. In post-menopausal women, serum creatinine level increased with increasing FSH quartile, which was accompanied by a decrease in estimated glomerular filtration rate (eGFR) (p for trend &lt;0.001); moreover, the prevalence of declined eGFR (&lt;90 ml/min/1.73 m2) and chronic kidney disease (CKD; eGFR &lt;60 ml/min/1.73 m2) increased (p for trend &lt;0.001). Even after adjusting for confounders, the odds ratios (ORs) of declined eGFR and CKD increased with increasing FSH quartiles in post-menopausal women. The ORs of declined eGFR (OR=2.19, 95% confidence interval [CI]: 1.63–2.92) and CKD (OR=10.09, 95% CI: 2.28–44.65) in the highest FSH quartile were approximately 2- and 10-fold higher, respectively, than in the lowest FSH quartile (p&lt;0.05). After stratifying post-menopausal women by median age (61 years), the OR for declined eGFR for each FSH quartile in the older group was higher than that for the corresponding FSH quartile in the younger group.ConclusionsA high circulating FSH level is an independent risk factor for renal dysfunction in women after menopause. Additionally, aging may aggravate the association of high FSH levels with reduced renal function in post-menopausal women