Hanmei Qi

Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue

Long-term glucocorticoid (GC) treatment induces central fat accumulation and metabolic dysfunction. We demonstrate that microRNA-27b (miR-27b) plays a central role in the pathogenesis of GC-induced central fat accumulation. Overexpression of miR-27b had the same effects as dexamethasone (DEX) treatment on the inhibition of brown adipose differentiation and the energy expenditure of primary adipocytes. Conversely, antagonizing miR-27b function prevented DEX suppression of the expression of brown adipose tissue–specific genes. GCs transcriptionally regulate miR-27b expression through a GC receptor–mediated direct DNA-binding mechanism, and miR-27b suppresses browning of white adipose tissue (WAT) by targeting the three prime untranslated region of Prdm16. In vivo, antagonizing miR-27b function in DEX-treated mice resulted in the efficient induction of brown adipocytes within WAT and improved GC-induced central fat accumulation. Collectively, these results indicate that miR-27b functions as a central target of GC and as an upstream regulator of Prdm16 to control browning of WAT and, consequently, may represent a potential target in preventing obesity.

BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice.

Background Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11β-HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11β-HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice. Methodology/Principal Findings C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro. Conclusions/Significance These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11β-HSD1 may be a very promising therapeutic target for obesity and associated disease.

Assessment of Fat distribution and Bone quality with Trabecular Bone Score (TBS) in Healthy Chinese Men.

Whether fat is beneficial or detrimental to bones is still controversial, which may be due to inequivalence of the fat mass. Our objective is to define the effect of body fat and its distribution on bone quality in healthy Chinese men. A total of 228 men, aged from 38 to 89 years, were recruited. BMD, trabecular bone score (TBS), and body fat distribution were measured by dual-energy X-ray absorptiometry. Subcutaneous and visceral fat were assessed by MRI. In the Pearson correlation analysis, lumbar spine BMD exhibited positive associations with total and all regional fat depots, regardless of the fat distribution. However, the correlation disappeared with adjusted covariables of age, BMI, HDL-C, and HbA1c%. TBS was negatively correlated with fat mass. In multiple linear regression models, android fat (and not gynoid, trunk, or limbs fat) showed significant inverse association with TBS (β = −0.611, P < 0.001). Furthermore, visceral fat was described as a pathogenic fat harmful to TBS, even after adjusting for age and BMI (β = −0.280, P = 0.017). Our findings suggested that body fat mass, especially android fat and visceral fat, may have negative effects on bone microstructure; whereas body fat mass contributes to BMD through mechanical loading.

Determination of UCP1 expression in subcutaneous and perirenal adipose tissues of patients with hypertension

The objective of this study is to determine the property of human perirenal adipose tissue (PAT) and assess the adipose property of PAT in hypertension. Ninety-four patients, including 64 normotensive patients (T-NP) and 30 hypertensive patients (HP), who underwent renal surgery were included. Expression analysis was performed using quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry in PAT and back subcutaneous adipose tissue (bSAT) depots. Compared with bSAT, PAT adipocytes were smaller, and the expressions of uncoupling protein-1 (UCP1) mRNA and protein were markedly higher, while the mRNA expressions of markers for classic beige and white adipocytes were lower in PAT. Immunohistochemistry analysis showed more multilocular UCP1-positive adipocytes in PAT than in bSAT. UCP1 expressions were lower in PAT in HP than in the T-NP or age- and body mass index-matched NP groups. Bigger unilocular adipocytes with less UCP1 staining in PAT were detected in HP than in NP group, although no such difference was observed in bSAT. PAT acts as a brown-like fat. UCP1 expression of PAT was lower in HP than in normotensive patients. UCP1 expression of PAT may serve as a protective indicator for hypertension.

Opposing effects on cardiac function by calorie restriction in different-aged mice

Calorie restriction (CR) increases average and maximum lifespan and exhibits an apparent beneficial impact on age‐related diseases. Several studies have shown that CR initiated either in middle or old age could improve ischemic tolerance and rejuvenate the aging heart; however, the data are not uniform when initiated in young. The accurate time to initiate CR providing maximum benefits for cardiac remodeling and function during aging remains unclear. Thus, whether a similar degree of CR initiated in mice of different ages could exert a similar effect on myocardial protection was investigated in this study. C57BL/6 mice were subjected to a calorically restricted diet (40% less than the ad libitum diet) for 3 months initiated in 3, 12, and 19 months. It was found that CR significantly reversed the aging phenotypes of middle‐aged and old mice including cardiac remodeling (cardiomyocyte hypertrophy and cardiac fibrosis), inflammation, mitochondrial damage, telomere shortening, as well as senescence‐associated markers but accelerated in young mice. Furthermore, whole‐genome microarray demonstrated that the AMP‐activated protein kinase (AMPK)–Forkhead box subgroup ‘O’ (FOXO) pathway might be a major contributor to contrasting regulation by CR initiated in different ages; thus, increased autophagy was seen in middle‐aged and old mice but decreased in young mice. Together, the findings demonstrated promising myocardial protection by 40% CR should be initiated in middle or old age that may have vital implications for the practical nutritional regimen.

MiR-27b-3p Regulation in Browning of Human Visceral Adipose Related to Central Obesity: MiR-27b-3p in Browning of Human VAT

Given the rising prevalence of central obesity and the discovery that beige cells appear within white adipose tissue, strategies to enhance these energy‐expending adipocytes or “browning” within white adipose depots have become of therapeutic interest to combat obesity and its associated disorders. This study focused on, the role of microRNA (miRNA)‐27b‐3p in human visceral adipose tissue (VAT) browning.

11β-hydroxysteroid dehydrogenase type 1 inhibitor attenuates high-fat diet induced cardiomyopathy

BACKGROUND High-fat diet (HFD) induces cardiac hypertrophy; however, the underlying cellular and molecular mechanisms are yet unclear. In the present study, we investigated the roles of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an amplifier of local glucocorticoid activity, in the pathogenesis of cardiac dysfunction. METHODS Male Wistar rats were fed normal chow diet (NC) or HFD and examined the cardiac remolding and functional alteration by echocardiography and histology. Primary neonatal rat ventricular cardiomyocytes (NRCMs) treated with palmitic acid (PA) or infected by lentivirus were used for identifying the role by 11β-HSD1 in cardiac hypertrophy. Genome microarray of NRCMs was performed to further reveal the mechanism underlying cardiac dysfunction. RESULTS Palmitic acid induced hypertrophy in NRCMs that upregulated 11β-HSD1 expression in cardiomyocytes, which led to a significant enlargement in the cell size and expression of cardiac hypertrophy-specific genes. Conversely, a remarkable decrease in cardiomyocytes size was detected in either BVT.2733 (a selective inhibitor of 11β-HSD1)-treated or 11β-HSD1-deficient NRCMs. Furthermore, both glucocorticoid receptor (GR) antagonist RU486 and mineralocorticoid receptor (MR) antagonist spironolactone markedly attenuated the 11β-HSD1-induced cardiomyocytes hypertrophy. Genome microarray revealed that cAMP and calcium signaling pathways are potential downstream signaling pathways regulated by 11β-HSD1 in cardiomyocytes hypertrophy. Similar to in vitro results, BVT.2733 strikingly attenuated cardiac hypertrophy and improved cardiac function in HFD-fed rats. CONCLUSION 11β-HSD1 acts as an important regulator that controls the cardiac remolding via both GR and MR and the pharmacological inhibition of 11β-HSD1 could be a new therapeutic approach in preventing HFD-induced cardiac hypertrophy.

Association of thyroid function with sarcopenia in elderly Chinese euthyroid subjects

ObjectivesWith the increase in aging population worldwide, the incidence of sarcopenia is also increasing. Thyroid hormones are important regulators that can affect body composition and physical function. The association between thyroid hormone levels and sarcopenia in susceptible elderly euthyroid subjects remains unclear. In this study, we investigated the effect of thyroid hormone concentrations on body muscle mass, muscle strength and physical function related to sarcopenia in elderly Chinese euthyroid subjects.MethodsA total of 94 elderly Chinese euthyroid subjects (73 men, 21 women) without medications or diseases which obviously affected muscle metabolism or thyroid function were included in our study. Concentrations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined by immunoassays. Appendicular skeletal muscle mass (ASM) was assessed by dual-energy X-ray absorptiometry. Handgrip strength was measured using a Jamar hand dynamometer, and physical function was assessed by the Short Physical Performance Battery (SPPB).ResultsMuscle function, both handgrip strength and SPPB, was negatively associated with age, and FT3 demonstrated age-dependent decline. Pearson’s correlation analysis showed positive associations of FT3 with ASM, handgrip strength and SPPB. Neither FT4 nor TSH was associated with these parameters of sarcopenia in euthyroid subjects. Significantly positive correlations between FT3 and ASM, handgrip strength and SPPB were also observed in multiple linear regression analysis adjusted for age, gender and BMI, while no significant correlations were found between FT4 or TSH and aforementioned four parameters of sarcopenia. Subjects with sarcopenia had lower level of FT3.ConclusionsHigher FT3 concentration within normal range was correlated to muscle mass and muscle function in elderly subjects.