BMAL1 deletion protects against obesity and non-alcoholic fatty liver disease induced by a high-fat diet.

OBJECTIVES: Obesity and non-alcoholic fatty liver disease (NAFLD) are major health concerns. The circadian rhythm is an autonomous and intrinsic timekeeping system closely associated with energy metabolism and obesity. Thus, this study explored the role of brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1), a circadian clock regulator, in the development of obesity and NAFLD. METHODS: We generated BMAL1 knockout (BMAL1 KO) mice to imitate circadian rhythm disruption. The study comprised three groups from the same litter: BMAL1 KO mice fed a high-fat diet (to establish obesity and NAFLD phenotypes), wild-type mice fed normal chow, and wild-type mice fed a high-fat diet. The metabolic and NAFLD phenotypes were assessed via physiological measurements and histological examinations. Quantitative polymerase chain reaction and western blotting were used to identify and validate changes in the signaling pathways responsible for the altered NAFLD phenotypes in the wild-type and BMAL1 KO mice. RESULTS: BMAL1 depletion protected against obesity and metabolic disorders induced by a high-fat diet. BMAL1 depletion also prevented hepatic steatosis and inhibited cluster of differentiation 36 and peroxisome proliferator-activated receptor gamma (i.e., PPARγ) expression. CONCLUSIONS: BMAL1 plays an important role in the development of obesity and NAFLD and, thus, is a potential therapeutic target for these conditions.

The research progress of crosstalk mechanism of autophagy and apoptosis in diabetic vascular endothelial injury.

In recent years, the widespread prevalence of diabetes has become a major killer that threatens the health of people worldwide. Of particular concern is hyperglycemia-induced vascular endothelial injury, which is one of the factors that aggravate diabetic vascular disease. During the process of diabetic vascular endothelial injury, apoptosis is an important pathological manifestation and autophagy is a key regulatory mechanism. Autophagy and apoptosis interact with each other. Hence, the crosstalk mechanism between the two processes is an important means of regulating diabetic vascular endothelial injury. This article reviews the research progress in apoptosis in the context of diabetic vascular endothelial injury and discusses the crosstalk mechanism of autophagy and apoptosis and its role in this injury. The purpose is to guide the prevention and treatment of diabetic vascular endothelial injury in the future.

Optimizing the number of valid measurements for the attenuation coefficient to assess hepatic steatosis in MAFLD patients: A study of 139 patients who underwent liver biopsy.

PURPOSE: We investigated the optimal number of valid measurements (VMs) for the attenuation coefficient (AC) to assess liver steatosis using attenuation imaging (ATI) and explored factors that may affect AC measurement in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). MATERIALS AND METHODS: A total of 139 patients with MAFLD who underwent ATI and liver biopsy were enrolled. Hepatic steatosis was graded as S0-3 according to the SAF scoring system. The AC values from 1, 2, 3, 5, and 7 VMs were compared with the degree of liver steatosis. The correlation between AC values from different VMs was analyzed. The diagnostic performance of AC from different VMs at each steatosis grade was compared. The factors related to AC were identified using linear regression analysis. RESULTS: The mean AC values from 1, 2, 3, 5, and 7 VMs were not significantly different between grades S0-3 (p=n.s. for all). Bland-Altman analysis showed the mean difference in AC values of 3 VMs and 7 VMs was 0.003 dB/cm/MHz, which was smaller compared with 2 VMs, and close to 5 VMs. The intraclass correlation coefficients of AC were all > 0.90 among different VM groups. AC values from different VMs all significantly predicted steatosis grade ≥S1, ≥S2, and S3 without significant statistical differences (p=n.s. for all). The multivariate analysis showed that the hepatic steatosis grade and triglyceride level were factors independently associated with AC. CONCLUSION: Three valid measurements of AC may be adequate to ensure the accuracy and reproducibility of hepatic steatosis assessment. The degree of liver steatosis and the triglyceride level significantly affected AC values.

Management and outcomes of gastric leak after sleeve gastrectomy: results from the 2010-2020 national registry.

BACKGROUND: Management of gastric leak after sleeve gastrectomy (SG) is challenging due to its unpredictable outcomes. We aimed to summarize the characteristics of SG leaks and analyze interventions and corresponding outcomes in a real-world setting. METHODS: To retrospectively review of 15,721 SG procedures from 2010 to 2020 based on a national registry. A cumulative sum analysis was used to identify a fitting curve of gastric leak rate. The Kaplan-Meier method and log-rank tests were performed to calculate and compare the probabilities of relevant outcomes. The logistic regression analysis was conducted to determine the predictors of acute leaks. RESULTS: A total of 78 cases of SG leaks were collected with an incidence of 0.5% (78/15,721) from this registry (6 patients who had the primary SG in non-participating centers). After accumulating 260 cases in a bariatric surgery center, the leak rate decreased to a stably low value of under 1.17%. The significant differences presented in sex, waist circumference, and the proportion of hypoproteinemia and type 2 diabetes at baseline between patients with SG leak and the whole registry population ( P = 0.005, = 0.026, <0.001, and = 0.001, respectively). Moreover, 83.1% (59/71) of the leakage was near the esophagogastric junction region. Leakage healed in 64 (88.9%, 64/72) patients. The median healing time of acute and non-acute leaks was 5.93 months and 8.12 months, respectively. Acute leak (38/72, 52.8%) was the predominant type with a cumulative reoperation rate >50%, whereas the cumulative healing probability in the patients who required surgical treatment was significantly lower than those requring non-surgical treatment ( P = 0.013). Precise dissection in the His angle area was independently associated with a lower acute leak rate, whereas preservation ≥2 cm distance from the His angle area was an independent risk factor. CONCLUSIONS: Male sex, elevated waist circumference, hypoproteinaemia, and type 2 diabetes are risk factors of gastric leaks after SG. Optimizing surgical techniques, including precise dissection of His angle area and preservation of smaller gastric fundus, should be suggested to prevent acute leaks.

A parabrachial-hypothalamic parallel circuit governs cold defense in mice.

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.

Sleeve gastrectomy decreases high-fat diet induced colonic pro-inflammatory status through the gut microbiota alterations.

Background: High-fat diet (HFD) induced obesity is characterized with chronic low-grade inflammation in various tissues and organs among which colon is the first to display pro-inflammatory features associated with alterations of the gut microbiota. Sleeve gastrectomy (SG) is currently one of the most effective treatments for obesity. Although studies reveal that SG results in decreased levels of inflammation in multiple tissues such as liver and adipose tissues, the effects of surgery on obesity related pro-inflammatory status in the colon and its relation to the microbial changes remain unknown. Methods: To determine the effects of SG on the colonic pro-inflammatory condition and the gut microbiota, SG was performed on HFD-induced obese mice. To probe the causal relationship between alterations of the gut microbiota and improvements of pro-inflammatory status in the colon following SG, we applied broad-spectrum antibiotics cocktails on mice that received SG to disturb the gut microbial changes. The pro-inflammatory shifts in the colon were assessed based on morphology, macrophage infiltration and expressions of a variety of cytokine genes and tight junction protein genes. The gut microbiota alterations were analyzed using 16s rRNA sequencing. RNA sequencing of colon was conducted to further explore the role of the gut microbiota in amelioration of colonic pro-inflammation following SG at a transcriptional level. Results: Although SG did not lead to pronounced changes of colonic morphology and macrophage infiltration in the colon, there were significant decreases in the expressions of several pro-inflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, IL-18, and IL-23 as well as increased expressions of some tight junction proteins in the colon following SG, suggesting an improvement of pro-inflammatory status. This was accompanied by changing populations of the gut microbiota such as increased richness of Lactobacillus subspecies following SG. Importantly, oral administrations of broad-spectrum antibiotics to delete most intestinal bacteria abrogated surgical effects to relieve colonic pro-inflammation. This was further confirmed by transcriptional analysis of colon indicating that SG regulated inflammation related pathways in a manner that was gut microbiota relevant. Conclusion: These results support that SG decreases obesity related colonic pro-inflammatory status through the gut microbial alterations.

Sleeve gastrectomy improved microvascular phenotypes from obesity cohort, detected with optical coherence tomography angiography.

AIMS: To examine how metabolic status is associated with microvascular phenotype and to identify variables associated with vascular remodeling after bariatric surgery, using noninvasive optical coherence tomography angiography (OCTA). METHODS: The study included 136 obese subjects scheduled for bariatric surgery and 52 normal-weight controls. Patients with obesity were divided into metabolically healthy obesity (MHO) and metabolic syndrome (MetS) groups according to the diagnosis criteria of the Chinese Diabetes Society. Retinal microvascular parameters were measured by OCTA, including superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel densities. Follow-ups were performed at the baseline and 6 months after bariatric surgery. RESULTS: Fovea SCP, average DCP, fovea DCP, parafovea DCP, and perifovea DCP vessel densities were significantly lower in the MetS group, compared to controls (19.91% vs. 22.49%, 51.60% vs. 54.20%, 36.64% vs. 39.14%, 56.24% vs. 57.65% and 52.59% vs. 55.58%, respectively, all p < .05). Parafovea SCP, average DCP, parafovea DCP, and perifovea DCP vessel densities significantly improved in patients with obesity 6 months after surgery, compared to baseline (54.21% vs. 52.97%, 54.43% vs. 50.95%, 58.29% vs. 55.54% and 55.76% vs. 51.82%, respectively, all p < .05). Multivariable analyses showed that baseline blood pressure and insulin were independent predictors of vessel density changes 6 months after surgery. CONCLUSIONS: Retinal microvascular impairment occurred mainly in MetS rather than MHO patients. Retinal microvascular phenotype improved 6 months after bariatric surgery and baseline blood pressure and insulin status may be key determinants. OCTA may be a reliable method to evaluate the microvascular complications associated with obesity.

Surgical strategies for recurrent parastomal hernia after a primary repair with a Dynamesh® IPST mesh.

PURPOSE: To introduce our surgical strategies for recurrent parastomal hernia after a primary repair with a Dynamesh® IPST mesh. METHODS: Ten patients who underwent recurrent parastomal hernia repair with previous Dynamesh® IPST mesh use were analyzed retrospectively. Distinct surgery strategies were applied. Accordingly, we investigated the recurrence rate and postoperative complications in these patients, who were followed for an average of 35.9 months after surgery. RESULTS: There was no recorded death and no readmission during the 30-day postoperative period. And the lap-re-do Sugarbaker group had no recurrence, whereas the open suture group had one recurrence (16.7%). One patient in the Sugarbaker group developed ileus and recovered conservatively during the follow-up period. There were no other complications, including seroma, mesh infection and bulging, or prolonged postoperative pain. CONCLUSIONS: We offer two predominant surgery strategies for recurrent parastomal hernia with a previous Dynamesh® IPST mesh usage, the open suture repair, and the Lap-re-do Sugarbaker repair. Even though the results of the Lap-re-do Sugarbaker repair are satisfactory, we recommend the open suture technique as it is safer in a setting of dense adhesions in recurrent parastomal hernias.

Hypothalamic warm-sensitive neurons require TRPC4 channel for detecting internal warmth and regulating body temperature in mice.

Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were thought to sense internal warmth, using this information as feedback to regulate body temperature (Tcore). However, the cellular and molecular mechanisms by which WSNs measure temperature remain largely undefined. Via a pilot genetic screen, we found that silencing the TRPC4 channel in mice substantially attenuated hypothermia induced by light-mediated heating of the POA. Loss-of-function studies of TRPC4 confirmed its role in warm sensing in GABAergic WSNs, causing additional defects in basal temperature setting, warm defense, and fever responses. Furthermore, TRPC4 antagonists and agonists bidirectionally regulated Tcore. Thus, our data indicate that TRPC4 is essential for sensing internal warmth and that TRPC4-expressing GABAergic WSNs function as a novel cellular sensor for preventing Tcore from exceeding set-point temperatures. TRPC4 may represent a potential therapeutic target for managing Tcore.

A Polysiloxane Delivery Vehicle of Cyclic N-Halamine for Biocidal Coating of Cellulose in Supercritical CO2.

Cyclic N-halamines are highly antimicrobial, very stable, and not susceptible to bacterial resistance. A polysiloxane delivery vehicle was synthesized to deliver cyclic imide N-halamine onto cellulose via a benign and universal procedure that does not require a harmful solvent or chemical bonding. In brief, Knoevenagel condensation between barbituric acid and 4-hydroxybenzaldehyde furnished 5-(4-hydroxybenzylidene)pyrimidine-2,4,6-trione, whose phenolic O-H was subsequently reacted with the Si-H of poly(methylhydrosiloxane) (PMHS) via silane alcoholysis. The product of silane alcoholysis was interpenetrated into cellulose in supercritical CO2 (scCO2) at 50 °C, to form a continuous modification layer. The thickness of the modification layer positively correlated with interpenetration pressure in the experimental range of 10 to 28 MPa and reached a maximum value of 76.5 nm, which demonstrates the ability for tunable delivery, to control the loading of the imide N-H bond originating from barbituric acid unit. The imide N-H bonds on cellulose with the thickest modifier were then chlorinated into N-Cl counterparts using tert-butyl hypochlorite, to exert a powerful biocidability, providing ~7 log reductions of both S. aureus and E. coli in 20 min. The stability and rechargeability of the biocidability were both very promising, suggesting that the polysiloxane modifier has a satisfactory chemical structure and interlocks firmly with cellulose via scCO2 interpenetration.

Quantitative Analysis of Abdominal Muscles Using Elastography in Female Patients With Incisional Hernia.

This study aimed to assess the thickness and shear wave speed (SWS) of the anterolateral abdominal wall muscles in female patients with incisional hernias of different widths, in order to analyze the biomechanical properties of abdominal wall muscles. This study included 53 patients with incisional hernia (Group A [hernia width <4 cm]: 21 patients, Group B [hernia width ≥4 cm]: 32 patients). The muscle thickness and SWS values of the external oblique (EO), internal oblique (IO), and transversus abdominis (TrA), and the hernia width were measured using Siemens Acuson S2000 ultrasound systems. Four detection points were labeled on the anterolateral abdominal wall: points 1, 2, 3, and 4, corresponding to the upper right, upper left, lower right, and lower left, respectively. The muscle thickness of the IO at point 3 was significantly different between both groups (p = 0.024). Group B had significantly higher SWS values than Group A, especially for the EO (points 1, 2, and 3), IO (points 1 and 2), and TrA (points 2 and 4) (p < 0.05). Pearson correlation analysis shows no significant correlation between muscle thickness and the SWS values of EO, IO, and TrA (all p > 0.05). Linear correlation analysis showed a significantly positive correlation between hernia width and the mean SWS value of EO, IO, and TrA (p = 0.004, 0.005, and 0.043, respectively). Muscle thickness was not reliable measure to directly reflect the biomechanical changes of the abdominal wall muscles in patients with incisional hernia. Comparatively, SWE can accurately measure the stiffness of the abdominal wall muscles and intuitively evaluate its biomechanical properties.

Vertical sleeve gastrectomy increases duodenal Lactobacillus spp. richness associated with the activation of intestinal HIF2α signaling and metabolic benefits.

OBJECTIVE: Vertical Sleeve Gastrectomy (VSG) is one of the most efficacious treatments for obesity and its comorbidities. Although a range of evidence suggests that alterations of the microbiota in the distal gut following VSG are pivotal to these metabolic improvements, the effect of surgery to alter the microbiota of the proximal intestine and its effect on host physiology remain largely unknown. As the main bacteria in the upper small intestine, Lactobacillus subspecies have been appreciated as important regulators of gut function. These bacteria also regulate intestinal Hypoxia- Inducible Factor 2α (HIF2α) signaling that plays an integral role in gut physiology and iron absorption. In the present study, we sought to determine the impact of VSG on Lactobacillus spp. in the small intestine and potential downstream impacts of Lactobacillus spp. on HIF2α, specifically in the duodenum. METHODS: To determine the effects of VSG on the microbiota and HIF2α signaling in the duodenum, VSG surgeries were performed on diet-induced obese mice. To further probe the relationship between Lactobacillus spp. and HIF2α signaling in the duodenum, we applied a customized high-fat but iron-deficient diet on mice to increase duodenal HIF2α signaling and determined alterations of gut bacteria. To explore the causal role of Lactobacillus spp. in duodenal HIF2α signaling activation, we chronically administered probiotics containing Lactobacillus spp. to high-fat-fed obese mice. Lastly, we studied the effect of lactate, the major metabolite of Lactobacilli, on HIF2α in ex vivo duodenal organoids. RESULTS: There were pronounced increases in the abundance of Lactobacillus spp. in samples isolated from duodenal epithelium in VSG-operated mice as compared to sham-operated mice. This was accompanied by an increase in the expression of genes that are targets of HIF2α in the duodenum of VSG-treated mice. Activating HIF2α signaling with a high-fat but iron-deficient diet resulted in weight loss, improvements in glucose regulation, and increased Lactobacillus spp. richness in the duodenum as compared to mice on an iron-replete diet. Chronic administration of probiotics containing Lactobacillus spp. not only increased HIF2α signaling in the duodenum such as occurs after VSG but also resulted in reduced weight gain and improved glucose tolerance in high-fat-fed mice. Furthermore, lactate was able to activate HIF2α in ex vivo duodenal organoids. CONCLUSIONS: These results support a model whereby VSG increases duodenal Lactobacillus richness and potentially stimulates intestinal HIF2α signaling via increased lactate production.

Bariatric surgery for non-alcoholic fatty liver disease in individuals with obesity (Base-NAFLD): protocol of a prospective multicenter observational follow-up study.

BACKGROUND: Bariatric surgery may be indicated in patients with nonalcoholic fatty liver disease (NAFLD) to achieve and maintain the degree of weight loss required to ensure therapeutic effects. However, bariatric surgery is still underrecognized in the treatment of NAFLD, including its inflammatory subtype, nonalcoholic steatohepatitis (NASH). Moreover, there is a lack of follow-up outcome data on different types of bariatric surgery in patients with NAFLD. This study aims to adequately assess the effect of bariatric surgery on NAFLD remission in obese patients. METHODS: This prospective multicentre observational follow-up study will include 142 obese patients with NAFLD scheduled to undergo one of the following surgical procedures: sleeve gastrostomy, Roux-en-Y gastric bypass, and one anastomosis gastric bypass. The primary outcome is the complete remission rate of NAFLD one year postoperatively, which is defined by liver fat fraction < 5% on magnetic resonance imaging; the secondary outcomes includes (i) changes in NASH and liver fibrosis biopsy findings, (ii) changes in body weight and abdominal adipose weight, (iii) resolution of obesity-related comorbidities, and (iv) incidence of adverse events. A long-term follow-up related to this study will also be conducted. DISCUSSION: This study will provide a necessary and preliminary foundation for the early identification and targeted treatment of patients with NAFLD who can be referred for bariatric surgery, as indicated for management of obesity and metabolic disease. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04366999. Registered 21 April 2020. ( https://clinicaltrials.gov/ct2/show/NCT04366999 ).

PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation.

BACKGROUND: The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin-proteasome inhibitor PS-341 could regulate the function of TM4. METHODS: The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. RESULTS: TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKß, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065-2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKß/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. CONCLUSIONS: PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.

Muscle elasticity is different in individuals with diastasis recti abdominis than healthy volunteers.

OBJECTIVE: To determine the value of shear wave elastography (SWE) in assessing abdominal wall muscles, including rectus abdominis (RA), external oblique muscle (EO), internal oblique muscle, and transversus abdominis (TrA) in patients with diastasis recti abdominis (DRA) and healthy controls. METHODS: From October 2018 to December 2019, 36 postpartum DRA patients and 24 nulliparous healthy women were identified. Inter-rectus distance (IRD) measurements were taken by B-mode ultrasound. Shear wave speed (SWS) values were acquired by one operator at ten specific locations. Clinical and ultrasound variables, including demographics, IRD, muscle thickness, and muscle SWS, were compared between the two groups using Student's t test or Fisher's exact test. Pearson correlation analyses were conducted for the variables of IRD, muscle thickness, and SWS in the 36 DRA patients. RESULTS: The maximum diameter of recti abdominus separation was located at the umbilicus in DRA patients (4.59 ± 1.14 cm). The SWS value was significantly lower in the RA (p = 0.003) and higher in the TrA muscle (p < 0.001) in DRA patients compared with the age-matched controls. However, SWS in both muscles (RA and TrA) showed a statistically positive correlation with IRD (p < 0.05). In addition, the SWS value in EO statistically decreased in DRA patients compared with the healthy controls (1.65 ± 0.15 vs. 1.79 ± 0.14, p = 0.001). CONCLUSIONS: The application of SWE to abdominal wall muscles in DRA patients is feasible. The correlation between SWS value and IRD in RA should be interpreted with caution.

Prediction of Long-Term Diabetes Remission After Metabolic Surgery in Obese East Asian Patients: a Comparison Between ABCD and IMS Scores.

PURPOSE: Recently, more than 10 models have been developed to predict remission of type 2 diabetes mellitus (T2DM) after metabolic surgery. The ABCD score was compared to the individualized metabolic surgery (IMS) score in terms of prediction of T2DM remission, but which of the two scoring systems is better remains controversial. METHODS: Patient data from 463 obese East Asian patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or SG with duodenojejunal bypass (SG-DJB) as a primary operation and were followed for at least 3 years were retrospectively collected from 24 institutions. The correlation between the ABCD and IMS scoring systems and the discrimination power of the models was evaluated. The cut-off point for the IMS stage of T2DM severity was also revised to adjust the scoring system to obese East Asian patients. RESULTS: The two scoring systems were significantly well correlated. The IMS scoring system showed significant differences in T2DM remission rates between the procedures in the moderate stage, but the ABCD score showed no significant differences in each category. The discrimination power of the IMS score was comparable to that of the ABCD score at both 3 and 5 years. The revised IMS scoring system showed that SG-DJB had significantly higher T2DM remission rates in the moderate stage at 5 years than RYGB or SG. CONCLUSION: IMS score may be comparable to ABCD score to predict T2DM remission in obese East Asian patients. The revised IMS scoring system may also select candidates for SG or SG-DJB.

Sleeve gastrectomy ameliorated high-fat diet (HFD)-induced non-alcoholic fatty liver disease and upregulated the nicotinamide adenine dinucleotide +/ Sirtuin-1 pathway in mice.

BACKGROUND: /Objective: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and effective treatments are lacking. Bariatric surgery, including sleeve gastrectomy (SG), is a potential therapeutic strategy for NAFLD, but the molecular mechanisms underlying its effects are not fully understood. In this study, the effects of SG and the underlying mechanisms were evaluated in a mouse model of high-fat diet (HFD)-induced NAFLD. METHODS: C57BL/6 mice were randomly divided into three groups: normal diet with sham operation (NC-Sham group), HFD with sham operation (HFD-Sham group), and HFD with sleeve gastrectomy (HFD-SG group). Glucose metabolism and fat accumulation in the body and liver were analyzed before and after SG. Lipid metabolism and inflammation in the liver were evaluated. Nicotinamide adenine dinucleotide (NAD+) levels as well as nicotinamide riboside kinase (NRK1) and Sirtuin-1 (SIRT1) expression levels were evaluated. RESULTS: SG attenuated the HFD-induced increases in glucose and insulin levels, fat accumulation, and lipid droplet accumulation. Fatty acid biosynthesis, the expression of the metabolism-related genes ACC1, FASN, SCD1, and DGAT1, and the levels of inflammatory factors were higher in HFD mice than in NC mice and decreased after SG. NAD + concentrations were 54.9 ± 13.4 µmol/mg in NC-Sham mice, 37.6 ± 8.1 µmol/mg in HFD-Sham mice, and 79.9 ± 13.0 µmol/mg in HFD-SG mice (p < 0.05). NRK1 and SIRT1 expression increased dramatically after SG at both the RNA and protein levels. CONCLUSION: SG significantly alleviated NAFLD in HFD-induced obese mice with increasing the hepatic NAD + levels and upregulating the NRK1/NAD+/SIRT1 pathway.

Cold-Inducible Klf9 Regulates Thermogenesis of Brown and Beige Fat.

Promoting development and function of brown and beige fat may represent an attractive treatment of obesity. In the current study, we show that fat Klf9 expression is markedly induced by cold exposure and a ß-adrenergic agonist. Moreover, Klf9 expression levels in human white adipose tissue (WAT) are inversely correlated with adiposity, and Klf9 overexpression in primary fat cells stimulates cellular thermogenesis, which is Ucp1 dependent. Fat-specific Klf9 transgenic mice gain less weight and have smaller fat pads due to increased thermogenesis of brown and beige fat. Moreover, Klf9 transgenic mice displayed lower fasting blood glucose levels and improved glucose tolerance and insulin sensitivity under the high-fat diet condition. Conversely, Klf9 mutation in brown adipocytes reduces the expression of thermogenic genes, causing a reduction in cellular respiration. Klf9-mutant mice exhibited obesity and cold sensitivity due to impairments in the thermogenic function of fat. Finally, fat Klf9 deletion inhibits the ß3 agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Klf9 stimulates expression of Pgc1α, a master regulator of fat thermogenesis, by a direct binding to its gene promoter region, subsequently promoting energy expenditure. The current study reveals a critical role for KLF9 in mediating thermogenesis of brown and beige fat.