bims-glecem 2022-04-17 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–04–17
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Effect of Different Carbohydrate Intakes within 24 Hours after Glycogen Depletion on Muscle Glycogen Recovery in Japanese Endurance Athletes.
Effect of Betaine and Arginine on Interaction of αB-Crystallin with Glycogen Phosphorylase b.
Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays.
To detect potential pathways and target genes in infantile Pompe patients using computational analysis.
What's new and what's next for gene therapy in Pompe disease?
Glycogen Branching Enzyme with a Novel Chain Transfer Mode Derived from Corallococcus sp. Strain EGB and Its Potential Applications.
Malignant glioma subset from actuate 1801: Phase I/II study of 9-ING-41, GSK-3β inhibitor, monotherapy or combined with chemotherapy for refractory malignancies.
[Myocardial biopsy of Liwen procedure: representability and etiological diagnostic value of cardiac samples obtained by a novel technique in patients with hypertrophic cardiomyopathy].
Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias.
Re-Expression of ERα and AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition.
Differentially expressed marker genes and glycogen levels in pectoralis major of Ross308 broilers with wooden breast syndrome indicates stress, inflammation and hypoxic conditions.
Reversal of NAFLD After VSG Is Independent of Weight-Loss but RYGB Offers More Efficacy When Maintained on a High-Fat Diet.
Quality More Than Quantity: The Use of Carbohydrates in High-Fat Diets to Tackle Obesity in Growing Rats.

Nutrients. 2022 Mar 22. pii: 1320. [Epub ahead of print]14(7):

Effect of Different Carbohydrate Intakes within 24 Hours after Glycogen Depletion on Muscle Glycogen Recovery in Japanese Endurance Athletes.

Keiko Namma-Motonaga, Emi Kondo, Takuya Osawa, Keisuke Shiose, Akiko Kamei, Motoko Taguchi, Hideyuki Takahashi.

  Daily muscle glycogen recovery after training is important for athletes. Few studies have reported a continuous change in muscle glycogen for 24 h. We aimed to investigate the changes in carbohydrate intake amount on muscle glycogen recovery for 24 h after exercise using 13C-magnetic resonance spectroscopy (13C-MRS). In this randomized crossover study, eight male participants underwent prolonged high-intensity exercise, and then consumed one of the three carbohydrate meals (5 g/kg body mass (BM)/d, 7 g/kg BM/d, or 10 g/kg BM/d). Glycogen content of thigh muscle was measured using 13C-MRS before, immediately after, and 4 h, 12 h and 24 h after exercise. Muscle glycogen concentration decreased to 29.9 ± 15.9% by exercise. Muscle glycogen recovery 4-12 h after exercise for the 5 g/kg group was significantly lower compared to those for 7 g/kg and 10 g/kg groups (p < 0.05). Muscle glycogen concentration after 24 h recovered to the pre-exercise levels for 7 g/kg and 10 g/kg groups; however, there was a significant difference for the 5 g/kg group (p < 0.05). These results suggest that carbohydrate intake of 5 g/kg BM/d is insufficient for Japanese athletes to recover muscle glycogen stores 24 h after completing a long-term high-intensity exercise.

Keywords:  13C-magnetic resonance spectroscopy; carbohydrate; exercise; glycogen; muscle; recovery

DOI:  https://doi.org/10.3390/nu14071320
Int J Mol Sci. 2022 Mar 30. pii: 3816. [Epub ahead of print]23(7):

Effect of Betaine and Arginine on Interaction of αB-Crystallin with Glycogen Phosphorylase b.

Tatiana B Eronina, Valeriya V Mikhaylova, Natalia A Chebotareva, Kristina V Tugaeva, Boris I Kurganov.

  Protein-protein interactions (PPIs) play an important role in many biological processes in a living cell. Among them chaperone-client interactions are the most important. In this work PPIs of αB-crystallin and glycogen phosphorylase b (Phb) in the presence of betaine (Bet) and arginine (Arg) at 48 °C and ionic strength of 0.15 M were studied using methods of dynamic light scattering, differential scanning calorimetry, and analytical ultracentrifugation. It was shown that Bet enhanced, while Arg reduced both the stability of αB-crystallin and its adsorption capacity (AC0) to the target protein at the stage of aggregate growth. Thus, the anti-aggregation activity of αB-crystallin increased in the presence of Bet and decreased under the influence of Arg, which resulted in inhibition or acceleration of Phb aggregation, respectively. Our data show that chemical chaperones can influence the tertiary and quaternary structure of both the target protein and the protein chaperone. The presence of the substrate protein also affects the quaternary structure of αB-crystallin, causing its disassembly. This is inextricably linked to the anti-aggregation activity of αB-crystallin, which in turn affects its PPI with the target protein. Thus, our studies contribute to understanding the mechanism of interaction between chaperones and proteins.

Keywords:  HspB5; aggregation; chemical chaperones; glycogen phosphorylase b; oligomeric structure

DOI:  https://doi.org/10.3390/ijms23073816
Int J Mol Sci. 2022 Mar 31. pii: 3856. [Epub ahead of print]23(7):

Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays.

Beatrice Balboni, Shailesh Kumar Tripathi, Marina Veronesi, Debora Russo, Ilaria Penna, Barbara Giabbai, Tiziano Bandiera, Paola Storici, Stefania Girotto, Andrea Cavalli.

  Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer's disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D 19F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.

Keywords:  Alzheimer’s disease; FBDD; NMR; cancer; drug discovery

DOI:  https://doi.org/10.3390/ijms23073856
Bioimpacts. 2022 ;12(2): 89-105

To detect potential pathways and target genes in infantile Pompe patients using computational analysis.

Aynur Karadağ Gürel, Selçuk Gürel.

  Introduction: Pompe disease (PD) is a disease caused by pathogenic variations in the GAA gene known as glycogen storage disease type II, characterized by heart hypertrophy, respiratory failure, and muscle hypotonia, leading to premature death if not treated early. The only treatment option, enzyme replacement therapy (ERT), significantly improves the prognosis for some patients while failing to help others. In this study, the determination of key genes involved in the response to ERT and potential molecular mechanisms were investigated. Methods: Gene Expression Omnibus (GEO) data, accession number GSE38680, containing samples of biceps and quadriceps muscles was used. Expression array data were analyzed using BRB-Array Tools. Biceps group patients did not receive ERT, while quadriceps received treatment with rhGAA at 0, 12, and 52 weeks. Differentially expressed genes (DEGs) were deeply analyzed by DAVID, GO, KEGG and STRING online analyses, respectively. Results: A total of 1727 genes in the biceps group and 1198 genes in the quadriceps group are expressed differently. It was observed that DEGs were enriched in the group that responded poorly to ERT in the 52nd week. Genes frequently changed in the weak response group; the expression of 530 genes increased and 1245 genes decreased compared to 0 and 12 weeks. The GO analysis demonstrated that the DEGs were mainly involved in vascular smooth muscle contraction, lysosomes, autophagy, regulation of actin cytoskeleton, inflammatory response, and the WNT signaling pathway. We also discovered that the WNT signaling pathway is highly correlated with DEGs. Several DEGs, such as WNT11, WNT5A, CTNNB1, M6PR, MYL12A, VCL, TLN, FYN, YES1, and BCL2, may be important in elucidating the mechanisms underlying poor response to ERT. Conclusion: Early diagnosis and treatment of PD are very important for the clinic of the disease. As a result, it suggests that the enriched genes and new pathways emerging as a result of the analysis may help identify the group that responds poorly to treatment and the outcome of the treatment. Obtained genes and pathways in neonatal screening will guide diagnosis and treatment.

Keywords:  Bioinformatics; Differentially expressed genes; Enzyme replacement treatment; GEO data; Pompe Disease; Wnt signaling pathway

DOI:  https://doi.org/10.34172/bi.2022.23467
Expert Opin Biol Ther. 2022 Apr 15.

What's new and what's next for gene therapy in Pompe disease?

Angela L Roger, Ronit Sethi, Meredith L Huston, Evelyn Scarrow, Joy Bao-Dai, Elias Lai, Debolina D Biswas, Léa El Haddad, Laura M Strickland, Priya S Kishnani, Mai K ElMallah.

   INTRODUCTION: Pompe disease is an autosomal recessive disorder caused by a deficiency of acid-⍺-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen. A lack of GAA leads to accumulation of glycogen in the lysosomes of cardiac, skeletal, and smooth muscle cells, as well as in the central and peripheral nervous system. Enzyme replacement therapy has been the standard of care for 15 years and slows disease progression, particularly in the heart, and improves survival. However, there are limitations of ERT success, which gene therapy can overcome.
AREAS COVERED: Gene therapy offers several advantages including prolonged and consistent GAA expression and correction of skeletal muscle as well as the critical CNS pathology. We provide a systematic review of the preclinical and clinical outcomes of adeno-associated viral mediated gene therapy and alternative gene therapy strategies, highlighting what has been successful.
EXPERT OPINION: Although the preclinical and clinical studies so far have been promising, barriers exist that need to be addressed in gene therapy for Pompe disease. New strategies including novel capsids for better targeting, optimized DNA vectors, and adjuctive therapies will allow for a lower dose, and ameliorate the immune response.

Keywords:  AAV; GAA; Pompe disease; acid alpha-glucosidase; gene therapy; neuromuscular disorder

DOI:  https://doi.org/10.1080/14712598.2022.2067476
J Agric Food Chem. 2022 Apr 11.

Glycogen Branching Enzyme with a Novel Chain Transfer Mode Derived from Corallococcus sp. Strain EGB and Its Potential Applications.

Xianfeng Ye, Wei Liu, Yuqi Liao, Tao Liu, Yuqiang Zhao, Yanxin Wang, Yu Zhang, Xu Li, Chengyao Xia, Xiaodong Fang, Yan Huang, Zhoukun Li, Zhongli Cui, Fei Wang.

  Dietary starch with an increased content of resistant starch (RS) has the potential to reduce the prevalence of diabetes, obesity, and cardiovascular diseases. Here, an efficient glycogen branching enzyme, CcGBE, from Corallococcus sp. strain EGB was identified, and its relevant properties, including potential application in the preparation of modified starch, were evaluated. The purified CcGBE exhibited a maximal specific activity of approximately 20,000 U/mg using cassava starch as the optimal substrate. The content of α-1,6-glucosidic bonds in CcGBE-modified cassava starch increased from 2.9 to 13.2%. Meanwhile, both the average chain length (CL) of CcGBE-modified starch and the blue value of the color complex formed by starch and iodine initially increased and then decreased, indicating that a new CL transfer mode was reported. Perforated small starch granules were released after CcGBE treatment, and a time-dependent decrease in the retrogradation enthalpy (ΔHr) of cassava starch indicated that CcGBE inhibited the long-term retrogradation of starch. Moreover, the RS content and cold water solubility (CWS) of CcGBE-modified starch increased from 3.3 to 12.8% and from 23.1 to 93.8%, respectively. These findings indicate the application potential of CcGBE for the preparation of modified starch with increased RS and CWS.

Keywords:  cassava starch; chain length distribution; glycogen branching enzyme; resistant starch; retrogradation

DOI:  https://doi.org/10.1021/acs.jafc.2c01621
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac012

Malignant glioma subset from actuate 1801: Phase I/II study of 9-ING-41, GSK-3β inhibitor, monotherapy or combined with chemotherapy for refractory malignancies.

Yazmin Odia, Ludimila Cavalcante, Howard Safran, Steven Francis Powell, Pamela N Munster, Wen Wee Ma, Benedito A Carneiro, Bruno R Bastos, Stacy Mikrut, William Mikrut, Francis J Giles, Solmaz Sahebjam.

   Background: GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3β inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect.
Methods: Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety.
Results: RP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30-69) years; 6 female, 12 male; median ECOG 1 (0-2); median recurrences 3 (1-6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4-305); 1 partial response (>50%) was noted. Median OS was 5.5 (95% CI: 2.8-11.4) months and PFS-6 was 16.7%.
Conclusion: 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

Keywords:  9-ING-41; GSK-3β; gliomas; lomustine; phase I trial

DOI:  https://doi.org/10.1093/noajnl/vdac012
Zhonghua Xin Xue Guan Bing Za Zhi. 2022 Apr 24. 50(4): 361-368

[Myocardial biopsy of Liwen procedure: representability and etiological diagnostic value of cardiac samples obtained by a novel technique in patients with hypertrophic cardiomyopathy].

C Han, M Y Zhou, J F Wu, B Wang, H Ma, R Hu, L Zuo, J Li, X J Li, S J Ta, L N Fan, L W Liu.

Objective: To investigate the representability and etiological diagnostic value of myocardium samples obtained from patients with hypertrophic cardiomyopathy (HCM) by transthoracic echocardiography-guided percutaneous intramyocardial septal biopsy (myocardial biopsy of Liwen procedure). Methods: This study was a retrospective case-series analysis. Patients with HCM, who underwent myocardial biopsy of Liwen procedure and radiofrequency ablation in Xijing Hospital, Air Force Military Medical University from July to December 2019, were included. Demographic data (age, sex), echocardiographic data and complications were collected through electronic medical record system. The histological and echocardiographic features, pathological characteristics of the biopsied myocardium of the patients were analyzed. Results: A total of 21 patients (aged (51.2±14.5) years and 13 males (61.9%)) were enrolled. The thickness of ventricular septum was (23.3±4.5)mm and the left ventricular outflow tract gradient was (78.8±42.6)mmHg (1 mmHg=0.133 kPa). Eight patients (38.1%) were complicated with hypertension, 1 patient (4.8%) had diabetes, and 2 patients (9.5%) had atrial fibrillation. Hematoxylin-eosin staining of myocardial samples of HCM patients before radiofrequency ablation evidenced myocytes hypertrophy, myocytes disarray, nuclear hyperchromatism, hypertrophy, atypia, coronary microvessel abnormalities, adipocyte infiltration, inflammatory cell infiltration, cytoplasmic vacuoles, lipofuscin deposition. Interstitial fibrosis and replacement fibrosis were detected in Masson stained biopsy samples. Hematoxylin-eosin staining of myocardial samples of HCM patients after radiofrequency ablation showed significantly reduced myocytes, cracked nuclear in myocytes, coagulative necrosis, border disappearance and nuclear fragmentation. Quantitative analysis of myocardial specimens of HCM patients before radiofrequency ablation showed that there were 9 cases (42.9%) with mild myocardial hypertrophy and 12 cases (57.1%) with severe myocardial hypertrophy. Mild, moderate and severe fibrosis were 5 (23.8%), 9 (42.9%) and 7 (33.3%), respectively. Six cases (28.6%) had myocytes disarray. There were 11 cases (52.4%) of coronary microvessel abnormalities, 4 cases (19.0%) of adipocyte infiltration, 2 cases (9.5%) of inflammatory cell infiltration,6 cases (28.5%) of cytoplasmic vacuole, 16 cases (76.2%) of lipofuscin deposition. The diameter of cardiac myocytes was (25.2±2.8)μm, and the percentage of collagen fiber area was 5.2%(3.0%, 14.6%). One patient had severe replacement fibrosis in the myocardium, with a fibrotic area of 67.0%. The rest of the patients had interstitial fibrosis. The myocardial specimens of 13 patients were examined by transmission electron microscopy. All showed increased myofibrils, and 9 cases had disorder of myofibrils. All patients had irregular shape of myocardial nucleus, partial depression, mild mitochondrial swelling, fracture and reduction of mitochondrial crest, and local aggregation of myofibrillary interfascicles. One patient had hypertrophy of cardiomyocytes, but the arrangement of muscle fibers was roughly normal. There were vacuoles in the cytoplasm, and Periodic acid-Schiff staining was positive. Transmission electron microscopy showed large range of glycogen deposition in the cytoplasm, with occasional double membrane surround, which was highly indicative of glycogen storage disease. No deposition of glycolipid substance in lysozyme was observed under transmission electron microscope in all myocardial specimens, which could basically eliminate Fabry disease. No apple green substance was found under polarized light after Congo red staining, which could basically exclude cardiac amyloidosis. Conclusion: Myocardium biopsied samples obtained by Liwen procedure of HCM patients are representative and helpful for the etiological diagnosis of HCM.

DOI: https://doi.org/10.3760/cma.j.cn112148-20220304-00146
Mol Genet Metab. 2022 Mar 28. pii: S1096-7192(22)00281-5. [Epub ahead of print]

Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias.

Teodoro Jerves, Nenad Blau, Carlos R Ferreira.

  Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.

Keywords:  Cancer; Inherited metabolic disease; Malignancy; Neoplasia; Oncometabolite

DOI:  https://doi.org/10.1016/j.ymgme.2022.03.011
Front Oncol. 2022 ;12 824594

Re-Expression of ERα and AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition.

Vikas Sharma, Jayadev Joshi, I-Ju Yeh, YongQiu Doughman, Daniel Blankenberg, David Wald, Monica M Montano.

  DNA methylation, catalyzed by DNA methyltransferase (DNMT), is a well-characterized epigenetic modification in cancer cells. In particular, promoter hypermethylation of AR and ESR1 results in loss of expression on Androgen Receptor (AR) and Estrogen Receptor (ER), respectively, and is associated with a hormone refractory state. We now report that Glycogen Synthase Kinase 3 (GSK3) phosphorylates DNMT1 at S714, which is localized to a 62 amino acid region referred to as auto-inhibitory linker, which functions to occlude the DNA from the active site of DNMT1 to prevent the methylation of unmethylated DNA. Molecular Dynamics simulation indicates that phosphorylation at S714 resulted in conformational rearrangement of the autoinhibitory domain that inactivated its ability to block the methylation of unmethylated DNA and resulted in enhanced DNA binding. Treatment with a novel and more selective inhibitor of GSK3 resulted in decreased methylation of the promoter region of genes encoding the Androgen Receptor (AR) and Estrogen Receptor alpha (ERa) and re-expression of the AR and ERa in AR negative prostate cancer and ER negative breast cancer cells, respectively. As a result, concurrent treatment with the GSK3 inhibitor resulted in responsiveness of AR negative prostate cancer and ER negative breast cancer cells to inhibitors of the AR or ER, respectively, in in vitro and in vivo experimental models.

Keywords:  Dnmt1; GSK3; androgen receptor; breast cancer; estrogen receptor; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2022.824594
Food Chem (Oxf). 2020 Oct 02. 1 100001

Differentially expressed marker genes and glycogen levels in pectoralis major of Ross308 broilers with wooden breast syndrome indicates stress, inflammation and hypoxic conditions.

Jette Feveile Young, Martin Krøyer Rasmussen.

  The occurrence of wooden breast (WB) in broiler production is increasing, but onset of its development is only described in part. In this study, we determined the regulation of marker genes related to oxidative stress in Ross308 broilers categorized as no-, mild- or severe-WB, on days 21 and 30 of production. The biochemical parameters, lactate dehydrogenase and pro- and macro-glycogen, were also determined. On day 21, breast meat from birds affected severely by WB had increased mRNA abundances of heat-shock protein 70, heme-oxygenase 1, cyclooxygenase 2, tumor necrosis factor 1, and hypoxia inducible factors as well as higher pH and lower dry matter contents. On day 30, breast meat from both mild and severely affected birds had increased mRNA for heme oxygenase 1, lactate dehydrogenase, and hypoxia inducible factor. Moreover, pro- and micro-glycogen, as well as the total pool of glycogen, were decreased compared with the non-WB birds. In conclusion, this study indicates oxidative stress, inflammation and hypoxic conditions in WB.

Keywords:  Biomarkers; Chicken; Meat; Muscle abnormalities; Muscle dystrophy; Poultry; Real time PCR; Wooden breast

DOI:  https://doi.org/10.1016/j.fochms.2020.100001
Obes Surg. 2022 Apr 14.

Reversal of NAFLD After VSG Is Independent of Weight-Loss but RYGB Offers More Efficacy When Maintained on a High-Fat Diet.

Ankita Srivastava, Matthew Stevenson, Jenny Lee, Christopher Hall, Thomas Palaia, Chaohui Lisa Zhao, Raymond Lau, Collin Brathwaite, Louis Ragolia.

PURPOSE: Bariatric surgery is emerging as an effective treatment for obesity and the metabolic syndrome. Recently, we demonstrated that Roux-en-Y gastric bypass (RYGB), but not vertical sleeve gastrectomy (VSG), resulted in improvements to white adipose physiology and enhanced brown adipose functioning. Since beneficial alterations to liver health are also expected after bariatric surgery, comparing the post-operative effects of RYGB and VSG on liver physiology is essential to their application in the treatment of non-alcoholic fatty liver disease (NAFLD).
MATERIALS AND METHODS: The effects of RYGB and VSG on liver physiology were compared using diet induced mouse model of obesity. High-fat diet (HFD) was administered for 12 weeks after surgery and alterations to liver physiology were assessed.
RESULTS: Both RYGB and VSG showed decreased liver weight as well as reductions to hepatic cholesterol and triglyceride levels. There were demonstrable improvements to NAFLD activity score (NAS) and fibrosis stage scoring after both surgeries. In RYGB, these beneficial changes to liver function resulted from the downregulation of pro-fibrotic and upregulation anti-fibrotic genes, as well as increased fatty acid oxidation and bile acid flux. For VSG, though similar alterations were observed, they were less potent. However, VSG did significantly downregulate pro-fibrotic genes and showed increased glycogen content paralleled by decreased glycogenolysis which may have contributed to the resolution of NAFLD.
CONCLUSION: RYGB and VSG improve liver physiology and function, but RYGB is more efficacious. Resolutions of NAFLD in RYGB and VSG are achieved through different processes, independent of weight loss.

DOI: https://doi.org/10.1007/s11695-022-06053-5
Front Nutr. 2022 ;9 809865

Quality More Than Quantity: The Use of Carbohydrates in High-Fat Diets to Tackle Obesity in Growing Rats.

Manuel Manzano, Maria D Giron, Rafael Salto, Jose D Vilchez, Francisco J Reche-Perez, Elena Cabrera, Azahara Linares-Pérez, Julio Plaza-Díaz, Francisco Javier Ruiz-Ojeda, Angel Gil, Ricardo Rueda, Jose M López-Pedrosa.

  Childhood obesity prevention is important to avoid obesity and its comorbidities into adulthood. Although the energy density of food has been considered a main obesogenic factor, a focus on food quality rather that the quantity of the different macronutrients is needed. Therefore, this study investigates the effects of changing the quality of carbohydrates from rapidly to slowly digestible carbohydrates on metabolic abnormalities and its impact on obesity in growing rats fed a high-fat diet (HFD). Growing rats were fed on HFD containing carbohydrates with different digestion rates: a HFD containing rapid-digesting carbohydrates (OBE group) or slow-digesting carbohydrates (ISR group), for 4 weeks and the effect on the metabolism and signaling pathways were analyzed in different tissues. Animals from OBE group presented an overweight/obese phenotype with a higher body weight gain and greater accumulation of fat in adipose tissue and liver. This state was associated with an increase of HOMA index, serum diacylglycerols and triacylglycerides, insulin, leptin, and pro-inflammatory cytokines. In contrast, the change of carbohydrate profile in the diet to one based on slow digestible prevented the obesity-related adverse effects. In adipose tissue, GLUT4 was increased and UCPs and PPARγ were decreased in ISR group respect to OBE group. In liver, GLUT2, FAS, and SRBP1 were lower in ISR group than OBE group. In muscle, an increase of glycogen, GLUT4, AMPK, and Akt were observed in comparison to OBE group. In conclusion, this study demonstrates that the replacement of rapidly digestible carbohydrates for slowly digestible carbohydrates within a high-fat diet promoted a protective effect against the development of obesity and its associated comorbidities.

Keywords:  growing rats; lipidomic analysis; metabolism; obesity; slow digestive carbohydrates

DOI:  https://doi.org/10.3389/fnut.2022.809865