Background: The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive. Methods: A case–control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD. Results: In morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition. Conclusions: This study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.

This study aimed to assess the effectiveness of metabolic and bariatric surgery (MBS) in patients with obesity comorbid with obesity hypoventilation syndrome (OHS) at 1-year follow-up. This retrospective study was conducted between January 2020 and June 2023 at an MBS center in a university-affiliated tertiary hospital in China. Clinical data, including body mass index (BMI), arterial blood gas (ABG) values, portable sleep study results, and anthropometric parameters, were recorded pre- and postoperatively. Correlations between variables and risk factors for OHS resolution were analyzed. Among 1134 MBS candidates, 187 (16.5%) had comorbid OHS;151 patients with OHS met inclusion criteria and completed the 1-year follow up visit (BMI 39.1 ± 6.8 kg/m² with PaCO₂ 48.6 ± 3.0 mmHg). At 1-year follow-up, BMI decreased to 29.0 ± 6.0 kg/m² (P<0.001) while PaCO₂ dropped to 43.8 ± 5.5 mmHg (P<0.001). Resolution of OHS, defined as awake PaCO₂ <45mmHg with discontinuation of PAP therapy for a minimum of 6 months before obtaining the ABG at the 12-month visit, was achieved in 105 (69.5%) of the patients. Nonlinear analysis indicated that PaCO₂ did not significantly decrease until percentage total weight loss (%TWL) exceeded approximately 20%. Larger reduction in waist circumference was associated with greater reduction in PaCO₂, particularly when waist circumference reached less than 25 cm. Beyond this point, ΔPaCO₂ plateaud. In multivariate analysis, larger preoperative waist circumference (OR: 1.046, 95% CI: 1.031-1.118, P = 0.025) and ABG pH < 7.35 (OR: 3.921, 95% CI: 2.305-9.140, P < 0.001) were associated with lack of resolution of OHS, while larger %TWL after bariatric surgery (OR: 0.917, 95% CI: 0.846-0.965, P = 0.001) was independently associated with OHS resolution. MBS is an effective treatment for OHS. Achieving a sufficient %TWL is critical for the resolution of OHS.

In mouse early pachytene spermatocytes, the X and Y chromosomes undergo rapid non-homologous (NH) synapsis and desynapsis, but the functional significance remains unknown. Here, we report that pachynema-specific knockout of Speedy A (SpdyA) from telomeres caused persistent Y-X NH synapsis , with the entire Y axis synapsed onto the X axis. This persistent Y-X NH synapsis did not interrupt meiotic sex chromosome inactivation, recombination, or sex body formation, but it disrupted X-Y loop-axis organization and homologous X-Y desynapsis, leading to spermatocyte death. Similarly, persistent Y-X NH synapsis was also observed in pachytene spermatocytes lacking TRF1, where SpdyA was frequently lost from the X-Y non-pseudoautosomal region (non-PAR) telomeres. Mechanistic studies revealed that Serine 48 of SUN1 is a key SpdyA/CDK2 phosphorylation site required for Y-X NH desynapsis. We propose that SpdyA governs Y-X NH desynapsis by stabilizing the linkage between the X-Y non-PAR telomeres and their LINC complexes, and that this process is regulated independently from other aspects of pachynema progression. Our findings suggest a key role for Y-X NH desynapsis in establishing proper X-Y loop-axis organization.

During meiosis, ZMM proteins play essential roles in stabilizing the recombination intermediates and promoting crossover (CO) formation. In mice, shortage in chiasmata 1 (SHOC1) forms a trimeric complex with the other two ZMM proteins, SPO16 and TEX11, to bind recombination intermediates after strand invasion. Although genetic variants of SHOC1 are clinically associated with male infertility, their conserved functions in human gametogenesis remain enigmatic. Here, we delineated species-specific divergences between human and mouse SHOC1 complex and identified a missense variant within the XPF-like domain in SHOC1 (p.Q590R). This variant impaired DNA double-strand breaks repair by compromising its ability to bind branched DNA structures and the recruitment of crucial proteins to recombination intermediates, ultimately abolishing CO formation. Furthermore, the variant disrupted dynamic chromatin structure in pachytene spermatocytes and induced synapsis defects. Importantly, the XPF-like domain in SHOC1 was revealed to prevent autosome intrusion into the sex body compartment, thereby protecting critical autosomal loci from meiotic silencing of unsynapsed chromatin (MSUC). Overall, our study underscores the critical role of the XPF-like domain in human SHOC1 in CO formation and in protecting autosomes from MSUC.