Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly suppressed to allow for glucose storage as glycogen and lipids in the liver. Failure to suppress gluconeogenesis after meals leads to elevated postprandial glucose levels, a key feature of type 2 diabetes. This dynamic switch is regulated by insulin and glucagon, but insulin resistance impairs this regulation. In this study, we identified a novel mechanism involving postprandial circulating hyaluronan (HA) and lysosomal hyaluronidase-1 (HYAL1) that suppresses hepatic gluconeogenesis by rewiring hepatic metabolism and mitochondrial function. Hyal1 knockout (Hyal1 KO) mice exhibited increased gluconeogenesis, while liver-specific Hyal1 overexpression (Liv-Hyal1) mice showed reduced gluconeogenic activity. Transcriptomic analysis revealed minimal changes in liver gene expression due to Hyal1 deletion, but metabolomic profiling demonstrated that Hyal1 overexpression mitigated high-fat diet (HFD)-induced elevations in gluconeogenic pathway metabolites. Mechanistically, HYAL1-mediated HA digestion activates a feedback loop in HA synthesis, repartitioning the cellular uridine diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) pool. This reduces O-linked N-acetylglucosamine modification (O-GlcNAcylation) of mitochondrial ATP synthase subunits, decreasing ATP production and suppressing gluconeogenesis. Importantly, this pathway remains intact in the livers of HFD-fed, insulin-resistant mice. In summary, our findings reveal a new postprandial mechanism for regulating hepatic gluconeogenesis, highlighting the potential of enhancing postprandial HA levels or hepatic HYAL1 activity as a therapeutic strategy for managing excessive gluconeogenesis in insulin-resistant conditions, such as type 2 diabetes.

Objective To develop and validate an individualized prediction model for risk of restenosis in patients with arteriosclerosis obliterans (ASO) after percutaneous transluminal angioplasty (PTA). Methods A case-control trial was conducted on 137 patients who received PTA treatment for ASO in the Department of Vascular Surgery of the First Affiliated Hospital of Chongqing Medical University from February 2020 to May 2022. Their clinical data were collected and analyzed. The patients were assigned into training set (n=97) and validation set (n=40) at a ratio of 7 ∶3. The primary endpoint was the occurrence of restenosis within 12 months after interventional procedure. Based on the training set, single and multiple factor Cox regression models were used to screen the independent influencing factors of restenosis within 12 months. Then the obtained regression coefficients were then employed to establish a prediction model and draw a nomogram. The data from the training and validation sets were adopted to validate the model internally and externally, and the area under the receiver operating characteristic curve (AUC) and calibration chart were used to evaluate the model's recognition. The decision curve chart was established to evaluate the benefit of using the model to treat patients. Results Intravascular ultrasound guidance, lesion type, preoperative residual outflow tract, lesion length, and intraoperative treatment were independent predictors of restenosis after PTA in ASO patients (P < 0.05) and included in the model. The AUC of the nomograph for model's internal validation was 0.84 (95%CI: 0.75~0.92), with a specificity and sensitivity of 0.797 and 0.737, respectively. The AUC of the external validation using the validation set was 0.86 (95%CI: 0.74~0.98), with a specificity and sensitivity of 0.963 and 0.615, respectively. The calibration curve in the 2 cohort groups showed that the predictive value of the nomogram matched the actual observation. The decision curve indicated that this model could significantly increase the net benefit to patients. Conclusion Our nomogram prediction model can predict vessel patency of ASO patient within 12 months after PTA, and it has been developed and validated as an individualized risk prediction model for this specific group.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR.

Background: High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins. Methods: Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4–10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4–10). Results: Echocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress. Conclusions: Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.

Hepatic gluconeogenesis is a crucial process to maintain glucose level during starvation. However, unabated glucose production in diabetic patients is a major contributor to hyperglycemia. Palmitoleic acid is a monounsaturated fatty acid (16:1n7) that is available from dietary sources. Palmitoleic acid exhibits health beneficial effects on diabetes, insulin resistance, inflammation, and metabolic syndrome. However, the mechanism by which palmitoleate reduces blood glucose is still unclear. SIRT3 is a key metabolism-regulating NAD+-dependent protein deacetylase. It is known that fasting elevates the expression of SIRT3 in the liver and it regulates many aspects of liver's response to nutrient deprivation, such as fatty acid oxidation and ketone body formation. However, it is unknown whether SIRT3 also regulates gluconeogenesis. Our study revealed that palmitoleic acid reduced hepatic gluconeogenesis and the expression of SIRT3 under high-fat diet conditions. Overexpression of SIRT3 in the liver and hepatocytes enhanced gluconeogenesis. Further study revealed that SIRT3 played a role in enhancing the activities of gluconeogenic enzymes, such as PEPCK, PC, and MDH2. Therefore, our study indicated that under a high-fat diet, palmitoleic acid decreased gluconeogenesis by reducing enzymatic activities of PEPCK, PC, and MDH2 by down-regulating the expression of SIRT3.

Objective: Although PU.1/Spi1 is known as a master regulator for macrophage development and function, we have reported previously that it is also expressed in adipocytes and is transcriptionally induced in obesity. Here, we investigated the role of adipocyte PU.1 in the development of the age-associated metabolic syndrome.Methods: We generated mice with adipocyte-specific PU.1 knockout, assessed metabolic changes in young and older adult PU.1fl/fl (control) and AdipoqCre PU.1fl/fl (aPU.1KO) mice, including body weight, body composition, energy expenditure, and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice.Results: aPU.1KO mice have elevated energy expenditure at a young age and decreased adiposity and increased insulin sensitivity in later life. Corroborating these observations, transcriptional network analysis indicated the existence of validated, adipocyte PU.1-modulated regulatory hubs that direct inflammatory and thermogenic gene expression programs.Conclusion: Our data provide evidence for a previously uncharacterized role of PU.1 in the development of age-associated obesity and insulin resistance.

Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of the mitogen-activated protein kinases and nuclear factor-κB signalling pathways. Furthermore, BBR decreased microRNA-155-5p secretion by macrophages, which in turn ameliorated liver injury. Moreover, BBR mitigated inflammatory responses in both LPS-stimulated macrophages and TNF-α-treated adipocytes and suppressed macrophage migration towards adipocytes by activating SIRT3. Collectively, this study revealed that BBR improved adipose tissue remodelling, and subsequently inhibited the secretion of microRNA-155-5p by macrophages, which alleviated adiposity, insulin resistance and liver injury in obese mice. The modulation of adipose tissue remodelling by activating SIRT3 could contribute to the anti-hyperlipidemic and anti-hyperglycemic effects of BBR.

Doxorubicin (DOX) is a chemotherapeutic with dose-dependent cardiotoxic effects that limits its use in patients. Previously we showed that DOX decreases expression of the mitochondrial lysine deacetylase SIRT3 in the mouse heart. We hypothesize that DOX impairs cardiac function and energy production through reduced SIRT3 and altered mitochondrial acetylation. We further hypothesize that increased SIRT3 expression could attenuate DOX-induced cardiac dysfunction via alterations of protein acetylation to enzymes involved in lipid remodeling and metabolic processes. Mice expressing cardiac restricted full length M1-SIRT3 (mitochondrial localized), and short M3-SIRT3 (lacking localization signal) received saline or DOX injections of 8 mg/kg body weight for 4 weeks and compared to non-transgenic (Non-Tg) littermates. Transthoracic echocardiography was performed on all mice (n=10). Total cardiac lipids were isolated from DOX treated cardiac tissue by chloroform:methanol extraction and global lipid analysis was performed by QTRAP LC-MS/MS (n=6). Cardiac mitochondria were and an anti-acetylated lysine antibody was used to enrich for tryptic digested peptides containing Acetyl-K and analyzed by QTRAP LC-MS/MS (n=6). In non-Tg mice, DOX caused cardiac dysfunction and expression of M1-SIRT3 and M3-SIRT3 transgenes in the heart preserved left ventricular posterior wall thickness (P<0.05) and ejection fraction (P<0.05) in DOX treated mice. Triglycerides and phospholipids (PE, PI, PC) were decreased in DOX treated mouse hearts while phosphatidylserine (PS), sphingomyelin and ganglioside (GM3) lipid species were increased (p<0.05). A negative correlation between decreased cardiac output and increased GM3 24:1 (R=-0.62, P<0.05), PS 38:4 levels (R=-0.81, P<0.005) and SM 35:1 (R=-0.65, P<0.05) was identified. 36 acetylated peptides involved in metabolic processes, oxidative stress resistance and lipid remodeling (eg. IDH2, SOD2, HADHA, P<0.05) were significantly altered in DOX-treated mice. Increased SIRT3 expression in the heart rescues DOX-induced cardiac dysfunction. DOX-induced cardiac dysfunction involved alterations in cardiac lipids and acetylated proteins that could be rescued by increased SIRT3 expression in the heart.

Studies suggest that biological sex influences susceptibility to kidney diseases with males demonstrating greater risk for developing ischemic acute kidney injury (AKI). Sex-related differences in mitochondrial function and homeostasis exist, likely contributing to sexual dimorphism in kidney injury, but the mechanisms are not well characterized. Our observations reveal lower baseline expression of Sirtuin-3 (Sirt3, a major mitochondrial acetyltransferase) in the kidneys of male mice versus females. We tested the hypothesis that differential expression of kidney Sirt3 may mediate sexual dimorphism in AKI using a bilateral kidney ischemia-reperfusion injury (IRI) model and three transgenic mouse models: (1) mice with global transgenic overexpression of Sirt3; (2) mice with inducible, kidney tubule-specific Sirt3 knockdown (iKD); and (3) mice with global Sirt3 knockout. Low mitochondrial Sirt3 (mtSirt3) in males versus females is associated with development of kidney tubular epithelium vacuoles, increased mitochondrial ROS and susceptibility to IRI. Transgenic overexpression of Sirt3 in males protects against kidney IRI and development of tubular epithelium vacuoles. In both sexes, mice with partial kidney tubular epithelium-specific Sirt3 knockdown display intermediate - while global Sirt3 knockout mice display the highest susceptibility to IRI. Female Sirt3 iKD mice demonstrate decreased survival and kidney function after IRI indistinguishable from control males, abolishing the protective effects observed in females. Mechanistically, observed differences in kidney mtSirt3 are sex hormone-dependent; estradiol increases - while testosterone decreases mtSirt3 protein. Our results demonstrate that Sirt3 is an important contributor to the observed sex-related differences in IRI susceptibility, and a potential therapeutic target in the clinical management of AKI.

Dynamin-Related-Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to β-adrenergic stimulation. To further investigate the function of DRP1 on ER-lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue-specific DRP1 knockout model (Adipo-Drp1flx/flx ). We found that the LDs in adipose tissues of Adipo-Drp1flx/flx mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro-LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo-Drp1flx/flx mice.

Obesity is increasing at an alarming rate worldwide, which is characterized by the excessive accumulation of triglycerides in adipocytes. Emerging evidence has demonstrated that macroautophagy and chaperone-mediated autophagy (CMA) regulate lipid mobilization and play a key role in energy balance. Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase, which is important in regulating macroautophagy and lipid metabolism. It is still unknown whether SIRT3 modulates macroautophagy and CMA in adipocytes. The current study found that macroautophagy was dynamically regulated during 3T3-L1 adipocyte differentiation, which coincided with SIRT3 expression. In mature adipocytes, overexpression of SIRT3 activated macroautophagy, mainly on lipid droplets (LDs), through activating the AMP-activated protein kinase (AMPK)-unc-51-like kinase 1 (ULK1) pathway, which in turn resulting in smaller LD size and reduced lipid accumulation. Moreover, SIRT3 overexpression induced the formation of perilipin-1 (PLN1)-heat shock cognate 71 kDa protein (HSC70)-lysosome-associated membrane protein 2 (LAMP2) complex, to activate CMA and cause the instability of LDs in adipocytes. In summary, we found SIRT3 is a positive regulator of macroautophagy and CMA in adipocytes, which might be a promising therapeutic target for treatment of obesity and its related metabolic dysfunction.

The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the α4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule-1 (VCAM1) on MSCs, leading to the activation of protein kinase C β1 (PKCβ1) signaling and repression of the muscle ring-finger protein-1 (MURF1)-mediated ubiquitylation of peroxisome proliferator-activated receptor γ2 (PPARγ2). Stabilized PPARγ2 proteins enhanced adipogenesis and consequently reduced osteoblastogenesis from MSCs, thus suppressing bone formation in vitro and in vivo. These findings reveal that suppressed bone formation is a direct consequence of myeloma-MSC contact that promotes the differentiation of MSCs into adipocytes at the expense of osteoblasts. Thus, this study provides a potential strategy for treating bone resorption in patients with myeloma by counteracting tumor-MSC interactions.

Marrow adipocytes reprogrammed by myeloma cells induce bone lesions.

Objective: Brown adipose tissue (BAT) is important for thermoregulation in many mammals. Uncoupling protein 1 (UCP1) is the critical regulator of thermogenesis in BAT. Here we aimed to investigate the deacetylation control of BAT and to investigate a possible functional connection between UCP1 and sirtuin 3 (SIRT3), the master mitochondrial lysine deacetylase. Methods: We carried out physiological, molecular, and proteomic analyses of BAT from wild-type and Sirt3K0 mice when BAT is activated. Mice were either cold exposed for 2 days or were injected with the beta 3-adrenergic agonist, CL316,243 (1 mg/kg; i.p.). Mutagenesis studies were conducted in a cellular model to assess the impact of acetylation lysine sites on UCP1 function. Cardiac punctures were collected for proteomic analysis of blood acylcarnitines. Isolated mitochondria were used for functional analysis of OXPHOS proteins. Results: Our findings showed that SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria, without affecting UCP1 expression. Acetylome profiling of BAT mitochondria revealed that SIRT3 regulates acetylation status of many BAT mitochondrial proteins including UCP1 and crucial upstream proteins. Mutagenesis work in cells suggested that UCP1 activity was independent of direct SIRT3-regulated lysine acetylation. However, SIRT3 impacted BAT mitochondrial proteins activities of acylcarnitine metabolism and specific electron transport chain complexes, CI and CII. Conclusions: Our data highlight that SIRT3 likely controls BAT thermogenesis indirectly by targeting pathways upstream of UCP1. (C) 2019 The Authors. Published by Elsevier GmbH.

Lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. Chaperon-mediated autophagy (CMA) triggers lipid droplets (LDs) breakdown, to initiate lipolysis via either cytosolic lipases or macroautophagy. SIRT3, a mitochondrial NAD(+)-dependent deacetylase, regulates the acetylation status and activity of many substrates involving in energy metabolism. However, the role of SIRT3 in regulating lipophagy is controversial. The current study showed that SIRT3 expression was decreased and the macroautophagy flux was blocked in the primary hepatocytes from high-fat diet fed mice and P/O (palmitic acid and oleic acid mixture) treated AML12 mouse hepatocytes, compared with the corresponding controls. SIRT3 overexpression promoted macroautophagy in LDs from P/O-treated hepatocytes through activating AMP-activated protein kinase (AMPK) and unc-51-like kinase 1, to boost LDs digestion. Gain of SIRT3 expression stimulated the formation of lysosome-associated membrane protein 2A (LAMP-2A)-heat shock cognate 71 kDa protein (HSC70)-perilipin-2 (PLN2) complex, to promote CMA process and reduce the stability of LDs in hepatocytes. Moreover, SIRT3 reduced the expression of stearoyl-CoA desaturase 1, to suppress lipogenesis. In addition, SIRT3 overexpression promoted LDs dispersion on detyrosinated microtubules, and directly deacetylated long-chain acylCoA dehydrogenase to enhance mitochondrial energetics. Taken together, SIRT3 ameliorates lipotoxicity in hepatocytes, which might be a potential target for the treatment of nonalcoholic fatty liver disease.

OBJECTIVE: To observe clinical efficacy and safety of febuxostat in the treatment of type 2 diabetic nephropathy complicated with hyperuricemia. METHODS: A total of 137 patients with type 2 diabetic nephropathy complicated with hyperuricemia selected from our hospital during Jan. 2014-Jun. 2016 were divided into group A (46 cases), B (47 cases), C (44 cases) according to random number table. On the basis of routine treatment, group A was given Allopurinol tablets orally with initial dose of 0. 05 g, bid; increasing to 0. 10 g, bid, 2 weeks later. Group B was given Benzbromarone tablets 50 mg orally, qd. Group C was given Febuxostat tablets orally with initial dose of 40 mg, qd; increasing to 80 mg, qd, 2 weeks later. All patients received treatment for consecutive 12 weeks. Clinical efficacies of 2 groups were observed, and the levels of serum uric acid (SUA), Scr and BUN were also observed before and after treatment. The occurrence of ADR was recorded. RESULTS: Four, six, three patients withdrew from the study in group A, B, C, respectively. The total response rates of group B, C (87. 8％, 85. 4％) were significantly higher than that of group A (76. 2％), with statistical significance (P＜0. 05); there was no statistical significance between group B and C (P＞0. 05). Before treatment, there was no statistical significance in the levels of SUA, Scr or BUN among 3 groups (P＞0. 05). Four weeks after treatment, the levels of SUA in 3 groups were decreased significantly compared to before treatment, with statistical significance (P＜0. 05); there was no statistical significance in other indexes among 3 groups or between before and after treatment (P＞0. 05). Twelve weeks after treatment, the levels of SUA in 3 groups were decreased significantly compared to before treatment and 4 weeks after treatment, and group B and C were significantly lower than group A; the levels of Scr in group A and C were decreased significantly compared to before treatment, while that of group B was increased significantly compared to before treatment and group B was significantly higher than group A and C, with statistical significance (P＜0. 05). There was no statistical significance in the levels of Scr or BUN among 3 groups compared to 4 weeks after treatment; there was also no statistical significance in the levels of SUA between group B and C, the levels of Scr between group A and C (P＞0. 05). Total incidence of ADR in group C (12. 20％) was significantly lower than group A and B (25. 58％, 24. 39％), with statistical significance (P＜0. 05); there was no statistical significance between group A and B (P＞0. 05). CONCLUSIONS: Febuxostat is better than allopurinol in reducing the level of SUA in type 2 diabetic nephropathy patients with hyperuricemia. It shows small effect on renal function with better safety.

FoxO1 and FoxO3a (collectively FoxO1/3a) proteins regulate a wide array of cellular processes, including hepatic gluconeogenesis. Phosphorylation of FoxO1/3a is a key event that determines its subcellular location and transcriptional activity. During glucose synthesis, the activity of FoxO1/3a is negatively regulated by Akt-mediated phosphorylation, which leads to the cytoplasmic retention of FoxO1/3a. However, the nuclear phosphatase that directly regulates FoxO1/3a remains to be identified. In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. We found that SCP4 enhanced the transcription of FoxO1/3a target genes encoding PEPCK1 and G6PC, key enzymes in hepatic gluconeogenesis. Ectopic expression of SCP4 increased, while knockdown of SCP4 inhibited, glucose production. Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice. Consistent with the positive role of SCP4 in gluconeogenesis, expression of SCP4 was regulated under pathophysiological conditions. SCP4 expression was induced by glucose deprivation in vitro and in vivo and was elevated in obese mice caused by genetic (Avy) and dietary (high-fat) changes. Thus, our findings provided experimental evidence that SCP4 regulates hepatic gluconeogenesis and could serve as a potential target for the prevention and treatment of diet-induced glucose intolerance and type 2 diabetes.

Oxidative stress contributes to the initiation and progression of liver damage. SIRT3 is a member of nicotinamide adenine dinucleotide-dependent deacetylases that plays a key role in anti-oxidative defense and mitochondrial function in the liver. Honokiol is a natural lignan from the plants of Magnolia genus that exhibits potent anti-oxidative property. This study aims to evaluate the hepatoprotective potential of honokiol against oxidative injury in tert-butyl hydroperoxide (t-BHP)-injured AML12 hepatocytes in vitro and carbon tetrachloride (CCl4)-stimulated liver damaged mice in vivo and to determine whether or not this effect occurs by activating SIRT3. The results showed honokiol protects t-BHP-injured AML12 hepatocytes and CCl4-stimulated liver damage in mice by activating SIRT3. Honokiol reduces the acetylation level of superoxide dismutase 2 to enhance its anti-oxidative capacity, which decreases reactive oxygen species accumulation in AML12 cells. Honokiol increases the deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α level to promote mitochondrial biogenesis. Moreover, honokiol attenuates t-BHP induced mitochondrial fragmentation through Ku70-dynamin-related protein 1 axis. These results suggest that honokiol can ameliorate oxidative damage in hepatocytes by activating SIRT3, which might be a potential therapeutic agent for liver oxidative injury.

Background & aims: The effect of maternal omega-3 fatty acids intake on the body composition of the offspring is unclear. The aim of this study was to conduct a systematic review and meta-analysis to confirm the effects of omega-3 fatty acids supplementation during pregnancy and/or lactation on body weight, body length, body mass index (BMI), waist circumference, fat mass and sum of skinfold thicknesses of offspring. Methods: Human intervention studies were selected by a systematic search of PubMed, Web of Science, the Cochrane Library and references of related reviews and studies. Randomized controlled trials of maternal omega-3 fatty acids intake during pregnancy or lactation for offspring's growth were included. The data were analyzed with RevMan 5.3 and Stata 12.0. Effect sizes were presented as weighted mean differences (WMD) or standardized mean difference (SMD) with 95% confidence intervals (95% CI). Results: Twenty-six studies comprising 10,970 participants were included. Significant increases were found in birth weight (WMD = 42.55 g, 95% CI: 21.25, 63.85) and waist circumference (WMD = 0.35 cm, 95% CI: 0.04, 0.67) in the omega-3 fatty acids group. There were no effects on birth length (WMD = 0.09 cm, 95% CI: -0.03, 0.21), postnatal length (WMD = 0.13 cm, 95% CI: -0.11, 0.36), postnatal weight (WMD = 0.04 kg, 95% CI: -0.07, 0.14), BMI (WMD = 0.09, 95% CI: -0.05, 0.23), the sum of skinfold thicknesses (WMD = 0.45 mm, 95% CI: -0.30, 1.20), fat mass (WMD = 0.05 kg, 95% CI: -0.01, 0.11) and the percentage of body fat (WMD = 0.04%, 95% CI: -0.38, 0.46). Conclusions: This meta-analysis showed that maternal omega-3 fatty acids supplementation can increase offspring's birth weight and postnatal waist circumference. However, it did not appear to influence children's birth length, postnatal weight/length, BMI, sum of skinfold thicknesses, fat mass and the percentage of body fat during postnatal period. Larger, well-designed studies are recommended to confirm this conclusion. (C) 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.