Hepatic LGR4 aggravates cholestasis-induced liver injury in mice.

Current therapy for hepatic injury induced by the accumulation of bile acids is limited. Leucine-rich repeat G protein-coupled receptor 4 (LGR4), also known as GPR48, is critical for cytoprotection and cell proliferation. Here, we reported a novel function for the LGR4 in cholestatic liver injury. In the bile duct ligation (BDL)-induced liver injury model, hepatic LGR4 expression was significantly downregulated. Deficiency of LGR4 in hepatocytes (Lgr4LKO) notably decreased BDL-induced liver injury measured by hepatic necrosis, fibrosis, and circulating liver enzymes and total bilirubin. Levels of total bile acids in plasma and liver were markedly reduced in these mice. However, deficiency of LGR4 in macrophages (Lyz2-Lgr4MKO) demonstrated no significant effect on liver injury induced by BDL. Deficiency of LGR4 in hepatocytes significantly attenuated S1PR2 and the phosphorylation of protein kinase B (AKT) induced by BDL. Recombinant Rspo1 and Rspo3 potentiated the taurocholic acid (TCA)-induced upregulation in S1PR2 and phosphorylation of AKT in hepatocytes. Inhibition of S1PR2-AKT signaling by specific AKT or S1PR2 inhibitors blocked the increase of bile acid secretion induced by Rspo1/3 in hepatocytes. Our studies indicate that the R-spondins (Rspos)-LGR4 signaling in hepatocytes aggravates the cholestatic liver injury by potentiating the production of bile acids in a S1PR2-AKT-dependent manner.NEW & NOTEWORTHY Deficiency of LGR4 in hepatocytes alleviates BDL-induced liver injury. LGR4 in macrophages demonstrates no effect on BDL-induced liver injury. Rspos-LGR4 increases bile acid synthesis and transport via potentiating S1PR2-AKT signaling in hepatocytes.

Nuclear Acly protects the liver from ischemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (IR) injury is the most common complication that occurs in liver surgery and hemorrhagic shock. ATP citrate lyase (Acly) plays a pivotal role in chromatin modification via generating acetyl-CoA for histone acetylation to influence biological processes. We aim to examine the roles of Acly, which is highly expressed in hepatocytes, in liver IR injury. APPROACH AND RESULTS: The functions of Acly in hepatic IR injury were examined in the mouse model with a hepatocyte-specific knockout of Acly . The Acly target genes were analyzed by CUT&RUN assay and RNA sequencing. The relationship between the susceptibility of the steatotic liver to IR and Acly was determined by the gain of function studies in mice. Hepatic deficiency of Acly exacerbated liver IR injury. IR induced Acly nuclear translocation in hepatocytes, which spatially fueled nuclear acetyl-CoA. This alteration was associated with enhanced acetylation of H3K9 and subsequent activation of the Foxa2 signaling pathway. Nuclear localization of Acly enabled Foxa2-mediated protective effects after hypoxia-reperfusion in cultured hepatocytes, while cytosolic Acly demonstrated no effect. The presence of steatosis disrupted Acly nuclear translocation. In the steatotic liver, restoration of Acly nuclear localization through overexpression of Rspondin-1 or Rspondin-3 ameliorated the IR-induced injury. CONCLUSIONS: Our results indicate that Acly regulates histone modification by means of nuclear AcCoA production in hepatic IR. Disruption of Acly nuclear translocation increases the vulnerability of the steatotic liver to IR. Nuclear Acly thus may serve as a potential therapeutic target for future interventions in hepatic IR injury, particularly in the context of steatosis.

Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/ß-catenin signaling pathway.

BACKGROUND: The leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) plays an important role in stem cell differentiation, organ development and cancer. Whether LGR4 affects the progression of hepatocellular carcinoma (HCC) remains unknown. This study aimed to reveal the role of LGR4 in HCC. METHODS: Clinical samples of HCC were collected to assess the expression of LGR4 and its correlation with patients' clinical characteristics. The expression level of LGR4 in HCC cells was altered by pharmacological and genetic methods, and the role of LGR4 in HCC progression was analyzed by in vivo and in vitro assays. HCC was induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) in wild-type and LGR4 deficient mice, the effect of LGR4 on HCC was examined by histopathological evaluation and biochemical assays. RESULTS: LGR4 expression was up-regulated in HCC samples, and its expression level was positively correlated with tumor size, microvascular invasion (MVI), TNM stage and pathological differentiation grade of HCC patients. In the mouse HCC model induced by DEN+CCl4, knockdown of LGR4 effectively inhibited the progression of HCC. Silencing of LGR4 inhibited the proliferation, migration, invasion, stem cell-like properties and Warburg effect of HCC cells. These phenotypes were promoted by R-spondin2 (Rspo2), an endogenous ligand for LGR4. Rspo2 markedly increased the nuclear translocation of ß-catenin, whereas IWR-1, an inhibitor of Wnt/ß-catenin signaling, reversed its effect. Deficiency of LGR4 significantly reduced the nuclear translocation of ß-catenin and the expression of its downstream target genes cyclinD1 and c-Myc. CONCLUSIONS: LGR4 promotes HCC progression via Wnt/ß-catenin signaling pathway.

Eliminating Institutional Barriers to Career Advancement for Diverse Faculty in Academic Surgery.

: There is critical need to address achievement barriers in Academic Medicine. Although opportunities for professional development of women and underrepresented minority physician scientists are growing, academic promotion rates remain historically low. Moreover, underrepresented groups are not likely to advance to decanal and leadership positions. To eliminate institutional barriers to achievement for diverse faculty, strategies to strengthen environment, recruitment, professional development, and leadership were implemented. This multifaceted approach is adaptable to Academic Surgery universally and we wish to share early progress.

Pilot Study to Evaluate the Safety, Feasibility, and Financial Implications of a Postoperative Telemedicine Program.

BACKGROUND: Telemedicine in surgery holds promise for improving access and decreasing costs, but its role remains ill-defined. This pilot study was performed to investigate the safety, feasibility, and financial implications of providing postoperative care using an electronic clinic (eClinic) at a university hospital. METHODS: An easy-to-use and secure eClinic platform was constructed in Epic (Epic Systems Corporation, Verona, WA). Patients undergoing laparoscopic cholecystectomy, appendectomy, and hernia repairs on an adult acute care surgery service were enrolled in this program over an 11-month period (March 2017 to January 2018). Patients with prolonged hospitalizations (greater than 4 nights), perioperative complications, drains, and open wounds were excluded. Demographics, clinical outcomes, encounter time, patient satisfaction survey results, and cost analysis were compared with the traditional clinic (tClinic) patient population. RESULTS: Two hundred thirty-three eligible patients (61% female; mean age 41 ±â€Š16 years) were enrolled in this program. Their demographics were no different than the tClinic. Frequencies of readmission, reoperation, and emergency department visits (2.7%, 0%, and 4.2%, respectively) in the eClinic group were also similar to the tClinic group. However, total visit time was significantly shorter in the eClinic group (14 vs 145 minutes, P < 0.01). Anonymous surveys demonstrated a high degree of satisfaction, with 85% of patients expressing desire to utilize the eClinic again. This program enhanced the capacity for new visits to tClinic, with a resultant projected increase in additional operative cases and revenue for the health care system. CONCLUSIONS: A safe and efficient postoperative telemedicine program can be constructed utilizing a widely available electronic medical record system, which can improve patient satisfaction, optimize throughput, and increase gross charges for the healthcare system.

Performance Metrics in Professional Baseball Pitchers before and after Surgical Treatment for Neurogenic Thoracic Outlet Syndrome.

BACKGROUND: High-performance throwing athletes may be susceptible to the development of neurogenic thoracic outlet syndrome (NTOS). This condition can be career-threatening but the outcomes of treatment for NTOS in elite athletes have not been well characterized. The purpose of this study was to utilize objective performance metrics to evaluate the impact of surgical treatment for NTOS in Major League Baseball (MLB) pitchers. METHODS: Thirteen established MLB pitchers underwent operations for NTOS between July 2001 and July 2014. For those returning to MLB, traditional and advanced (PitchF/x) MLB performance metrics were acquired from public databases for various time-period scenarios before and after surgery, with comparisons made using paired t-tests, Wilcoxon matched-pair signed-rank tests, and Kruskal-Wallis analysis of variance. RESULTS: Ten of 13 pitchers (77%) achieved a sustained return to MLB, with a mean age of 30.2 ± 1.4 years at the time of surgery and 10.8 ± 1.5 months of postoperative rehabilitation before the return to MLB. Pre- and postoperative career data revealed no significant differences for 15 traditional pitching metrics, including earned run average (ERA), fielding independent pitching, walks plus hits per inning pitched (WHIP), walks per 9 innings, and strikeouts to walk ratio (SO/BB). There were also no significant differences between the 3 years before and the 3 years after surgical treatment. Using PitchF/x data for 72 advanced metrics and 25 different time-period scenarios, the highest number of significant relationships (n = 18) was observed for the 8 weeks before/12 weeks after scenario. In this analysis, 54 (75%) measures were unchanged (including ERA, WHIP, and SO/BB) and 14 (19%) were significantly improved, while only 4 (6%) were significantly decreased (including hard pitch maximal velocity 93.1 ± 1.0 vs. 92.5 ± 0.9 miles/hr, P = 0.047). Six pitchers remained active in MLB during the study period, while the other 4 had retired due to factors or injuries unrelated to NTOS. CONCLUSIONS: Objective performance metrics demonstrate that pitchers returning to MLB after surgery for NTOS have had capabilities equivalent to or better than before treatment. Thoracic outlet decompression coupled with an ample period of postoperative rehabilitation can provide effective treatment for professional baseball pitchers with career-threatening NTOS.

Designing a leadership development program for surgeons.

BACKGROUND: Although numerous leadership development programs (LDPs) exist in health care, no programs have been specifically designed to meet the needs of surgeons. This study aimed to elicit practicing surgeons' motivations and desired goals for leadership training to design an evidence-based LDP in surgery. MATERIALS AND METHODS: At a large academic health center, we conducted semistructured interviews with 24 surgical faculty members who voluntarily applied and were selected for participation in a newly created LDP. Transcriptions of the interviews were analyzed using analyst triangulation and thematic coding to extract major themes regarding surgeons' motivations and perceived needs for leadership knowledge and skills. Themes from interview responses were then used to design the program curriculum specifically to meet the leadership needs of surgical faculty. RESULTS: Three major themes emerged regarding surgeons' motivations for seeking leadership training: (1) Recognizing key gaps in their formal preparation for leadership roles; (2) Exhibiting an appetite for personal self-improvement; and (3) Seeking leadership guidance for career advancement. Participants' interviews revealed four specific domains of knowledge and skills that they indicated as desired takeaways from a LDP: (1) leadership and communication; (2) team building; (3) business acumen/finance; and (4) greater understanding of the health care context. CONCLUSIONS: Interviews with surgical faculty members identified gaps in prior leadership training and demonstrated concrete motivations and specific goals for participating in a formal leadership program. A LDP that is specifically tailored to address the needs of surgical faculty may benefit surgeons at a personal and institutional level.

Restaging of locally advanced rectal cancer with magnetic resonance imaging and endoluminal ultrasound after preoperative chemoradiotherapy: a systemic review and meta-analysis.

BACKGROUND: Magnetic resonance imaging and endoluminal ultrasound play an important role in the restaging of locally advanced rectal cancer after preoperative chemoradiotherapy, yet their diagnostic accuracy is still controversial. OBJECTIVE: Meta-analysis was performed to estimate the diagnostic performance of MRI and endoluminal ultrasound. DATA SOURCES: Electronic databases from 1996 to March 2012 were searched. STUDY SELECTION AND INTERVENTIONS: Either MRI or endoluminal ultrasound was used to restage rectal cancer after chemoradiotherapy or radiation. MAIN OUTCOME MEASURES: T category, lymph node, and circumferential resection involvement were measured. RESULTS: The sensitivity estimate for rectal cancer diagnosis (T0) by endoluminal ultrasound (37.0%; 95% CI, 24.0%-52.1%) was higher (p = 0.04) than the sensitivity estimate for MRI (15.3%; 95% CI, 6.5%-32.0%). For T3-4 category, sensitivity estimates of MRI and endoluminal ultrasound were comparable, 82.1% and 87.6%, whereas specificity estimates were poor (53.5% and 66.4%). For lymph node involvement, there was no significant difference between the sensitivity estimates for MRI (61.8%) and endoluminal ultrasound (49.8%). Specificity estimates for MRI and endoluminal ultrasound were 72.0% and 78.7%. For circumferential resection margin involvement, MRI sensitivity and specificity were 85.4% and 80.0%. LIMITATIONS: To identify the heterogeneity, metaregression was performed on covariates. However, few of the covariates were identified to be statistically significant because of the lack of adequate original data. CONCLUSION: Accurate restaging of locally advanced rectal cancer by MRI and endoluminal ultrasound is still a challenge. Identifying T0 rectal cancer by imaging is not reliable. Before performing surgery, restaging is important, but some of the T0-2 patients are likely overestimated as T3-4. Both modalities for lymph node involvement are not very good. Magnetic resonance imaging may be a good method to reassess circumferential resection margin.

Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.

Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

Modulation of food intake by mTOR signalling in the dorsal motor nucleus of the vagus in male rats: focus on ghrelin and nesfatin-1.

Previous studies have demonstrated that mammalian target of rapamycin (mTOR) signalling in the hypothalamus is involved in the control of energy homeostasis. The aim of this study was to characterize the effect of mTOR signalling in the dorsal motor nucleus of the vagus (DMNV) on energy intake. Phospho-mTOR was detected in the DMNV neurons, and its levels were increased by energy deprivation. Rapamycin significantly inhibited mTOR activity and reduced food intake when administrated into the fourth ventricle. Exposure of DMNV neurons to ghrelin increased the phosphorylation of mTOR. Injection of ghrelin into the fourth ventricle significantly increased food intake relative to the control vehicle. Pretreatment with rapamycin for 15 min attenuated the orexigenic effect of ghrelin. A reduction in the phosphorylation of mTOR was observed following injection of nesfatin-1 into the fourth ventricle. When administrated by injection into the fourth ventricle, nesfatin-1 suppressed food intake in comparison with the control vehicle. The anorexigenic effect of nesfatin-1 was significantly attenuated by pretreatment with leucine for 15 min. All these findings suggest that mTOR signalling in the DMNV neurons regulates both the nutrient and the hormonal signals for the modulation of food intake.

Analytic morphometric assessment of patients undergoing colectomy for colon cancer.

BACKGROUND: Analytic morphometrics provides objective data that may better stratify risk. We investigated morphometrics and outcome among colon cancer patients. METHODS: An IRB-approved review identified 302 patients undergoing colectomy who had CT scans. These were processed to measure psoas area (PA), density (PD), subcutaneous fat (SFD), visceral fat (VF), and total body fat (TBF). Correlation with complications, recurrence, and survival were obtained by t-tests and linear regression models after adjusting for age and Charlson index. RESULTS: The best predictor of surgical complications was PD. PMH, Charlson, BMI, and age were not significant when PD was considered. SF area was the single best predictor of a wound infection. While all measures of obesity correlated with outcome, TBF was most predictive. Final multivariate Cox models for survival included age, Charlson score, nodal positivity, and TBF. CONCLUSIONS: Analytic morphometric analysis provided objective data that stratified complications and outcome better than age, BMI, or co-morbidities.

Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats.

Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected into the fourth intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose sufficient to inhibit food intake. Nesfatin-1 (2 µg) inhibited dark-phase food intake, in a dose-dependent fashion, for >3 h. Gastric acid production was evaluated in urethane-anesthetized rats. Nesfatin-1 (2 µg) was introduced via the 4V following endocrine stimulation of gastric acid secretion by pentagastrin (2 µg·kg(-1)·h(-1) iv), vagal stimulation with 2-deoxy-D-glucose (200 mg/kg sc), or no stimulus. Gastric secretions were collected via gastric cannula and neutralized by titration to determine acid content. Nesfatin-1 did not affect basal and pentagastrin-stimulated gastric acid secretion, whereas 2-deoxy-D-glucose-stimulated gastric acid production was inhibited by nesfatin-1 in a dose-dependent manner. c-Fos immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by nesfatin-1 administered via the 4V. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold increase in the mean number of c-Fos-positive neurons in the dorsal motor nucleus of the vagus (DMNV) in nesfatin-1-treated animals vs. controls (P < 0.01). Finally, nesfatin-induced Ca(2+) signaling was evaluated in primary cultured DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent Ca(2+) increments in 95% of cultured DMNV neurons. These studies demonstrate that central administration of nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally stimulated secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers Ca(2+) signaling in cultured DMNV neurons.

mTOR-dependent modulation of gastric nesfatin-1/NUCB2.

BACKGROUND: Nesfatin-1, an 82 amino acid peptide derived from the prohormone nucleobindin-2 (NUCB2), is a novel satiety hormone acting through a leptin-independent mechanism in the hypothalamus. The mechanisms by which production of nesfatin-1/NUCB2 is regulated remain unknown. METHODS: Nesfatin-1/NUCB2 mRNA and immunoreactivity were examined in gastric tissue and Min-6 cells by RT-PCR and immunofluorescent staining or Western blotting. RESULTS: Nesfatin-1/NUCB2 is co-localized with pS6K1, the downstream target of mammalian target of rapamycin (mTOR), in gastric X/A like cells. A parallel relationship between gastric mTOR signaling and nesfatin-1/NUCB2 was observed during changes in energy status. Both mTOR activity and gastric nesfatin-1/NUCB2 were down-regulated by fasting, and returned to basal levels with re-feeding. In high fat diet induced obese mice, gastric mTOR signaling and nesfatin-1/NUCB2 were increased. Inhibition of the gastric mTOR signaling by rapamycin attenuated the expression of gastric nesfatin-1/NUCB2 mRNA and protein in both lean and obese mice. Attenuation of mTOR activity by rapamycin or over-expression of TSC1 or TSC2 reduced the expression of nesfatin-1/NUCB2 in Min-6 cells, suggesting a direct effect of mTOR signaling. CONCLUSION: Gastric mTOR is a gastric energy sensor whose activity is linked to the regulation of gastric nesfatin-1/NUCB2.

Ankyrin repeat and SOCS box containing protein 4 (Asb-4) colocalizes with insulin receptor substrate 4 (IRS4) in the hypothalamic neurons and mediates IRS4 degradation.

BACKGROUND: The arcuate nucleus of the hypothalamus regulates food intake. Ankyrin repeat and SOCS box containing protein 4 (Asb-4) is expressed in neuropeptide Y and proopiomelanocortin (POMC) neurons in the arcuate nucleus, target neurons in the regulation of food intake and metabolism by insulin and leptin. However, the target protein(s) of Asb-4 in these neurons remains unknown. Insulin receptor substrate 4 (IRS4) is an adaptor molecule involved in the signal transduction by both insulin and leptin. In the present study we examined the colocalization and interaction of Asb-4 with IRS4 and the involvement of Asb-4 in insulin signaling. RESULTS: In situ hybridization showed that the expression pattern of Asb-4 was consistent with that of IRS4 in the rat brain. Double in situ hybridization showed that IRS4 colocalized with Asb-4, and both Asb-4 and IRS4 mRNA were expressed in proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons within the arcuate nucleus of the hypothalamus. In HEK293 cells co-transfected with Myc-tagged Asb-4 and Flag-tagged IRS4, Asb-4 co-immunoprecipitated with IRS4; In these cells endogenous IRS4 also co-immunoprecipitated with transfected Myc-Asb-4; Furthermore, Asb-4 co-immunoprecipitated with IRS4 in rat hypothalamic extracts. In HEK293 cells over expression of Asb-4 decreased IRS4 protein levels and deletion of the SOCS box abolished this effect. Asb-4 increased the ubiquitination of IRS4; Deletion of SOCS box abolished this effect. Expression of Asb-4 decreased both basal and insulin-stimulated phosphorylation of AKT at Thr308. CONCLUSIONS: These data demonstrated that Asb-4 co-localizes and interacts with IRS4 in hypothalamic neurons. The interaction of Asb-4 with IRS4 in cell lines mediates the degradation of IRS4 and decreases insulin signaling.

Regulation of food intake and body weight by recombinant proghrelin.

Ghrelin is a 28-amino-acid hormone derived from the endoproteolytic processing of its prehormone proghrelin. Although ghrelin has been reported to regulate food intake and body weight, it is still unknown whether proghrelin exercises any biological function. Here we show that recombinant proghrelin alters food intake and energy metabolism in mice. After intraperitoneal administration of recombinant proghrelin (100 nmol/kg body wt), cumulative food intake was significantly increased at days 1, 2, and 3 (6 +/- 0.3, 13 +/- 0.5, and 20 +/- 0.8 g vs. 5 +/- 0.2, 10 +/- 0.2, and 16 +/- 0.3 g of the control mice receiving normal saline, respectively, n = 6, P < 0.05). Twelve-hour cumulative food intake in the light photo period in mice treated with proghrelin increased significantly relative to the control (2.1 +/- 0.04 vs. 1.3 +/- 0.2 g, n = 6, P < 0.05). No change in 12-h cumulative food intake in the dark photo period was observed between mice treated with proghrelin and vehicle (4.2 +/- 0.6 vs. 4.3 +/- 0.6 g, n = 6, P > 0.05). This is associated with a decrease in body weight (0.42 +/- 0.04 g) for mice treated with proghrelin, whereas control animals gained body weight (0.31 +/- 0.04 g). Mice treated with proghrelin demonstrate a significant decrease in respiratory quotient, indicating an increase in fat consumption. Recombinant proghrelin is functionally active with effects on food intake and energy metabolism.

Building High-Performing Teams in Academic Surgery: The Opportunities and Challenges of Inclusive Recruitment Strategies.

PROBLEM: In academic surgery, women and physicians from ethnic minority groups remain inadequately represented relative to their representation in the U.S. population and among medical students and surgical trainees. Although several initiatives have been aimed at developing the academic surgery pipeline or addressing issues related to faculty retention and promotion, little is known about how recruitment practices impact diversity in academic medicine. Moreover, national standards and ideal practices specific for effective recruitment in surgery have not been established. APPROACH: A working group at the Department of Surgery at the University of Michigan implemented an inclusive search and selection process for all open faculty positions within the department in academic year 2017-2018. The strategy included mandatory training, a standing recruitment committee with diverse membership, broad promotion of positions, implementing a modified "Rooney rule," panel interviews of candidates, standardized interview protocols, a standardized evaluation tool and scoring system, and written evaluations/ranking of candidates. OUTCOMES: Implementation of this recruitment strategy resulted in several immediate measurable benefits including increased diversity of the applicant pools and of new faculty hires. In addition to these positive effects, the department noted several knowledge gaps and faced challenges to implementing all elements of the strategy. NEXT STEPS: The authors share their framework, highlighting opportunities and challenges that are broadly generalizable and relevant for building high-performing teams in academic medicine. Work to set measurable metrics and address challenges for inclusive recruitment in surgery is ongoing. Such evaluation and refinement are important for sustainability and increasing effectiveness.

Effect of des-acyl ghrelin on adiposity and glucose metabolism.

Ghrelin, a gastric peptide hormone, has been reported to regulate GH secretion and energy homeostasis. Here, we examined the effect of des-acyl ghrelin driven from the fatty acid-binding protein-4 (FABP4) promoter on adiposity and glucose metabolism. A high level of expression of des-acyl ghrelin (692 +/- 293 fmol/g fat) in adipose tissue was detected in FABP4-ghrelin transgenic mice, but not in wild-type littermates. Circulating des-acyl ghrelin was significantly higher in FABP4-ghrelin transgenic mice (8409 +/- 3390 pm) compared with wild-type mice (513 +/- 58 pm). No significant change was observed for plasma acylated ghrelin and obestatin. Epididymal and perirenal fat masses decreased 35 +/- 9 and 52 +/- 9%, respectively, in FABP4-ghrelin transgenic mice. FABP4-ghrelin transgenic mice are resistant to obesity induced by high-fat diet. Brown fat mass was not affected by overexpression of ghrelin in adipose tissue. Glucose tolerance tests showed glucose levels to be significantly lower in FABP4-ghrelin transgenic mice than in controls after glucose administration. Insulin sensitivity testing showed that FABP4-ghrelin transgenic mice had a 28 +/- 5% greater hypoglycemic response to insulin. Our study demonstrates that overexpression of ghrelin from the FABP4 promoter impairs the development of white adipose tissues, and alters glucose tolerance and insulin sensitivity in mice.

Ankyrin repeat and SOCS box containing protein 4 (Asb-4) interacts with GPS1 (CSN1) and inhibits c-Jun NH2-terminal kinase activity.

Asb-4 is a gene that is specifically expressed in the hypothalamic energy homeostasis-associated areas and is down-regulated in the arcuate nucleus of fasted Sprague Dawley and obese Zucker rats. It has two functional domains, the ankyrin repeat and the SOCS box. The function of Asb-4 is unclear. We used yeast two hybridization to search for protein(s) that interact with Asb-4. With Asb-4 minus its SOCS box (Asb-4/Deltasb) as a bait, we screened mouse testis and arcuate nucleus cDNA libraries and identified G-protein pathway suppressor 1 (GPS1, also known as CSN1) as an Asb-4 interacting protein. GPS1 co-immunoprecipitated with Asb-4 both in vitro and in human HEK293 cells. When Asb-4 and GPS1 were co-transfected into HEK293 cells, expression of Asb-4 reduced the protein level of GPS1. Deletion of the SOCS box (Asb4/Deltasb) did not abolish the inhibitory effect of Asb-4 on GPS1, indicating that the SOCS box was not needed for its inhibitory effect. In NIH 3T3 L1 cells, expression of GPS1 enhanced c-Jun NH2-terminal kinase (JNK) activity. Co-expression of Asb-4 with GPS1 inhibited JNK activity. Treatment of the cells with insulin (20 nM) stimulated JNK activity. Expression of GPS1 potentiated the stimulatory effect of insulin, whereas co-expression of Asb-4 along with GPS1 inhibited JNK activity. In HEK293 cells expression of GPS1 elevated phosphorylation of insulin receptor substrate 1 (IRS-1) at serine307, co-expression of Asb-4 with GPS1 reduced the IRS-1ser307 phosphorylation. The present study demonstrates that Asb-4 interacts with GPS1 and inhibits JNK activity.