Physiological Functions of FBW7 in Metabolism.

FBW7 is the recognition subunit of the SCF (Skp1-Cullin1-F-box proteins) E3 ubiquitin ligase complex, and it determines the specificity of the SCF substrate. SCFFBW7 is a recognized tumor suppressor because of its ability to degrade many proto-oncogenic substrates. Recent studies have shown that FBW7 plays a key role in metabolism by targeting the degradation of critical regulators involved in cellular metabolism in a ubiquitin-dependent manner. Here, we review recent studies, which highlight the important role of FBW7 in metabolism.

FSH modulated cartilage ECM metabolism by targeting the PKA/CREB/SOX9 pathway.

INTRODUCTION: Osteoarthritis (OA) is a common joint disease characterized by articular cartilage degeneration. The prevalence of OA is higher among women than men, and this prevalence is closely related to menopause. The classic view assumes that the underlying mechanism of postmenopausal OA is attributed to declining estrogen levels. Although follicle-stimulating hormone (FSH) levels become elevated in parallel, the effects of FSH on OA have been poorly explored. The present study aimed to study the effect of FSH on cartilage metabolism. METHODS: Chondrocyte-like ATDC5 cells were treated with recombinant FSH protein. Then the cell viability was measured using cell counting kit-8 assay. Expressions of crucial factors involved in the extracellular matrix (ECM) metabolic and PKA-CREB-SOX9 pathway were analyzed by western blot, RT-qPCR, and immunofluorescence staining. Intracellular cAMP levels were assessed by ELISA assay. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) surgery. Adeno-associated virus expressing shRNA against FSHR (AAV-shFSHR) was intra-articular (IA) injected into the OA model animals to specifically knock down FHSR in cartilage. Histological staining and OARSI scores were used to assess the efficacy of AAV-shFSHR injections. RESULTS: We found that FSH down-regulated the expression of ECM-related proteins in chondrocyte-like ATDC5 cells. The underlying mechanism is probably associated with regulating PKA/CREB/SOX9 pathway. Besides, blocking FSH signaling via shRNA-mediated downregulation of FSHR in joint tissues effectively delayed the development of posttraumatic OA in mice. CONCLUSIONS: Our results collectively indicated that FSH plays an essential role in the pathogenesis of OA and acts as a crucial mediator.

Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice.

AIMS/HYPOTHESIS: Increased serum follicle-stimulating hormone (FSH) is correlated with fasting hyperglycaemia. However, the underlying mechanism remains unclear. Because excessive hepatic gluconeogenesis is a major cause of fasting hyperglycaemia the present study investigated whether FSH increases hepatic gluconeogenesis in mice. METHODS: Ovariectomised mice supplemented with oestradiol (E2) to maintain normal levels of serum E2 (OVX+E2 mice) were injected with low or high doses of FSH. We knocked out Crtc2, a crucial factor in gluconeogenesis, and Fshr to discern their involvement in FSH signalling. To evaluate the role of the G-protein-coupled receptor (GPCR) kinase 2 (GRK2), which could affect glucose metabolism and interact directly with non-GPCR components, a specific GRK2 inhibitor was used. The pyruvate tolerance test (PTT), quantification of PEPCK and glucose-6-phosphatase (G6Pase), key enzymes of gluconeogenesis, GRK2 and phosphorylation of AMP-activated protein kinase (AMPK) were examined to evaluate the level of gluconeogenesis in the liver. A nonphosphorylatable mutant of AMPK Ser485 (AMPK S485A) was transfected into HepG2 cells to evaluate the role of AMPK Ser485 phosphorylation. RESULTS: FSH increased fasting glucose (OVX+E2+high-dose FSH 8.18 ± 0.60 mmol/l vs OVX+E2 6.23 ± 1.33 mmol/l), the PTT results, and the transcription of Pepck (also known as Pck1; 2.0-fold increase) and G6pase (also known as G6pc; 2.5-fold increase) in OVX+E2 mice. FSH also enhanced the promoter luciferase activities of the two enzymes in HepG2 cells. FSH promoted the membrane translocation of GRK2, which is associated with increased AMPK Ser485 and decreased AMPK Thr172 phosphorylation, and enhanced the nuclear translocation of cyclic AMP-regulated transcriptional coactivator 2 (CRTC2). GRK2 could bind with AMPK and induce Ser485 hyperphosphorylation. Furthermore, either the GRK2 inhibitor or AMPK S485A blocked FSH-regulated AMPK Thr172 dephosphorylation and gluconeogenesis. Additionally, the deletion of Crtc2 or Fshr abolished the function of FSH in OVX+E2 mice. CONCLUSIONS/INTERPRETATION: The results indicate that FSH enhances CRTC2-mediated gluconeogenesis dependent on AMPK Ser485 phosphorylation via GRK2 in the liver, suggesting an essential role of FSH in the pathogenesis of fasting hyperglycaemia.

Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes.

OBJECTIVE: Chondrocytes express many kinds of hormone receptors. The function of Follicle stimulating hormone (FSH) in the ovary is mediated by FSH receptor (FSHR). FSH receptor (FSHR) is found in many non-ovarian tissues, however it has been unclear if chondrocytes express FSHR. The purpose of this study is to determine it. METHODS: Mouse primary chondrocytes and human articular cartilage tissues were examined. The expression and sequence of FSHR mRNA by reverse transcription polymerase chain reaction (RT-PCR) and sequenced, respectively, and its protein expression was tested using western blotting and location was observed under immunofluorescence microscopy. Ovarian tissue was as a positive control. After FSH stimulated mouse chondrocytes, intracellular cAMP levels were assessed by ELISA, and gene expression relative to Mouse WNT Signaling Pathway was tested by RT2 Profiler PCR Arrays. RESULTS: FSHR was detected at the transcriptional level and confirmed to have the same sequence as that of ovary-derived mRNA of FSHR. FSHR proteins presented at the same line as the positive proteins of ovary, in mouse chondrocytes and human cartilage tissue, respectively. FSHR proteins were located at the cell membrane. Intracellular cAMP contents were significantly elevated up to 7-fold in mouse chondrocytes by forskolin (100 mM) (P < 0.001); however, different doses of FSH did not change the cAMP contents in mouse primary chondrocytes. RT2 Profiler PCR Arrays demonstrated that FSH could cause changes in gene expression among the 84 preordained genes, such as Fosl1, Rhou, and Dkk1, in mouse chondrocytes relative to the control. CONCLUSION: Mouse chondrocytes and human articular cartilage express functional FSHR. Moreover, FSH can act on chondrocytes and cause genetic changes.

Quantum frequency down-conversion of bright amplitude-squeezed states.

We demonstrate experimentally the quantum frequency down-conversion of a bright amplitude-squeezed optical field via a high efficiency difference frequency generation process. 532 nm amplitude-squeezed light with squeezing of 1.0 dB is successfully translated to 810 nm amplitude-squeezed light with squeezing of 0.8 dB. The effects of amplitude and phase fluctuations of the pump field on the frequency conversion are investigated both theoretically and experimentally. It is shown that the quantum frequency down-conversion is insensitive to small amplitude fluctuations of the pump field at the optimal conversion point. However, the phase fluctuations of the pump field can lead to increase of noise in the phase quadrature of the down-converted field. To eliminate the additive phase noise, a dual frequency down-converter which utilizing common pump field is proposed and demonstrated.

FNDC5/Irisin in dementia and cognitive impairment: update and novel perspective.

Epidemiological surveys show that the incidence of age-related dementia and cognitive impairment is increasing and it has been a heavy burden for society, families, and healthcare systems, making the preservation of cognitive function in an increasingly aging population a major challenge. Exercise is beneficial for brain health, and FDNC5/irisin, a new exercise-induced myokine, is thought to be a beneficial mediator to cognitive function and plays an important role in the crosstalk between skeletal muscle and brain. This review provides a critical assessment of the recent progress in both fundamental and clinical research of FDNC5/irisin in dementia and cognitive impairment-related disorders. Furthermore, we present a novel perspective on the therapeutic effectiveness of FDNC5/irisin in alleviating these conditions.

Epidemiology of lean/non-obese nonalcoholic fatty liver disease in China: A systematic review and meta-analysis.

OBJECTIVES: To assess the prevalence and metabolic characteristics of lean/non-obese (L/NO) nonalcoholic fatty liver disease (NAFLD) in China. METHODS: The databses, inlcuding PubMed, Web of Science, EMBASE, as well as Cochrane databases, were retrieved for eligible studies. The prevalence together with clinical features of L/NO-NAFLD in China were analyzed using a random/fixed effects model. Lean or nonobese participants were characterized by the cut-offs of body mass index used in original studies. Heterogeneity was identified using meta-regression and subgroup analyses. RESULTS: We included 25 studies for the final analysis comprising 229091 L/NO Chinese adults and 22641 diagnosed with NAFLD, with the NAFLD prevalence of 8.98% (95% confidence interval [CI]: [5.55-13.13] for L-NAFLD Chinese participants and 13.77% (95% CI: [11.13-16.63]) for NO-NAFLD Chinese participants. This prevalence gradually increased during the past few years. The community and health checkup populations presented similar prevalence (14.19% vs. 13.55%). Meanwhile, L/NO patients with NAFLD showed lower blood pressure (128.86/80.48 vs. 136.09/84.98 mmHg), waist circumference (80.63 vs. 92.73 cm), fasting blood glucose (5.53 vs. 5.69 mmol/L), uric acid (339.14 vs. 365.46 µmol/L), triglyceride levels (1.63 vs. 1.94 mmol/L), alanine transaminase (30.28 vs. 33.12 IU/L), and γ-glutamyl transferase (29.9 vs. 43.68 IU/L), but higher levels of high-density lipoprotein cholesterol (1.33 vs. 1.26 mmol/L) compared to overweight/obese (OW/O) patients with NAFLD. CONCLUSION: Prevalence of NAFLD was slightly lower among the L/NO-NAFLD Chinese population than the global level but has obviously increased recently. In addition, the metabolic profile of L/NO-NAFLD patients was generally better compared to OW/O-NAFLD patients.PROSPERO Reg. No.: CRD42022327240.

FSH directly regulates chondrocyte dedifferentiation and cartilage development.

Previous studies suggest that postmenopausal osteoarthritis is linked to a decrease in estrogen levels. However, whether follicle-stimulating hormone (FSH), the upstream hormone of estrogen, affects cartilage destruction and thus contributes to the onset of osteoarthritis has never been explored. To evaluate the potential involvement of FSH in joint degeneration and to identify the molecular mechanisms through which FSH influences chondrocytes, mouse cartilage chondrocytes and the ATDC5 chondrocyte cell line were treated with FSH and inhibitors of intracellular signaling pathways. We observed that FSH induces chondrocyte dedifferentiation by decreasing type II collagen (Coll-II) synthesis. Chondrocyte cytoskeleton reorganization was also observed after FSH treatment. The FSH-induced decrease in Coll-II was rescued by ERK-1/2 inhibition but aggravated by p38 inhibition. In addition, knocking down the FSH receptor (Fshr) by using Fshr siRNA abolished chondrocyte dedifferentiation, as indicated by the increased expression of Coll-II. Inhibition of the protein Gαi by pertussis toxin (PTX) also restored FSH-inhibited Coll-II, suggesting that Gαi is downstream of FSHR in chondrocyte dedifferentiation. FSHß antibody blockade prevented cartilage destruction and cell loss in mice. Moreover, decreased Coll-II staining due to the progression of aging could be rescued by blocking FSH. Thus, we suggest that high circulating FSH, independent of estrogen, is an important regulator in chondrocyte dedifferentiation and cartilage destruction.

High follicle-stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF-κB pathway.

Osteoarthritis is the main cause of pain and disability in the elderly, with the most commonly affected joint being the knee. The prevalence of knee osteoarthritis (KOA) is significantly increased in postmenopausal women, although the mechanisms underlying KOA remain unclear. The present study aimed to investigate the association between follicle-stimulating hormone (FSH) and postmenopausal women with KOA aged between 50 and > 70 years, as well as explore its underlying molecular mechanisms. Here, we report that the 50-60 years age group had the highest level of serum FSH. Compared to the low FSH group (< 40 mIU·mL-1 ) in the same age group, the high FSH group (> 40 mIU·mL-1 ) showed more severe cartilage damage. Furthermore, phosphorylated (p)-phosphoinositide 3-kinase (PI3K)/PI3K, p-AKT/AKT and p-nuclear factor kappa B (NF-κB)/NF-κB levels were significantly higher in the high FSH group compared to the low FSH group. Immunofluorescence experiments showed that FSH stimulation promoted the translocation of NF-κB p65 into the nucleus, and decreased type II collagen and aggrecan in ATDC5 cells. Moreover, we used western blotting in ATDC5 cells to demonstrate that FSH decreased type II collagen and increased p-PI3K/PI3K, p-AKT/AKT, p-NF-κB/NF-κB and p-IKB/IKB in a concentration-dependent manner. Our results suggest that increased FSH levels are associated with KOA for postmenopausal women aged 50-60 years and that high FSH levels might damage the cartilage tissues through the PI3K/AKT/NF-κB pathway.