Biology subjects

Tavakkoli, A.

Publications and source records attributed to Tavakkoli, A..

7 recordsLinked to original sources

bioRxiv2025

Vitamin D receptor is necessary for metabolic health after sleeve gastrectomy

BackgroundThe vitamin D receptor (VDR) regulates insulin sensitivity. Metabolic bariatric surgery (MBS) remains the most effective treatment for obesity and T2D. However, whether its metabolic effects are VDR-dependent is unknown. Here, we assessed VDR role in the metabolic response to sleeve gastrectomy (SG). MethodsWhole body VDR knockout (KO) and wild type (WT) C57BL/6J mice with diet-induced obesity (DIO) were assigned to either SG or sham procedure. Postoperatively, animals underwent glucose and insulin tolerance tests. On sacrifice, serum, white adipose tissue (WAT), liver and colonic contents were collected for further biochemical, histological and bile acid analysis. Separately, human VDR gene expression was assessed in subcutaneous adipose tissue (SAT) biopsies collected from patients with/without MBS history. ResultsKO SG mice exhibited delayed glucose utilization after an oral challenge and progressive loss of insulin sensitivity, despite the same magnitude of surgery-induced weight change between the two genotypes. WAT in KO SG mice had lower mass, smaller adipocytes and increased inflammation. SG had a differential effect on colonic levels of the glucoregulatory cholic acid 7-sulfate (CA7S): increasing CA7S concentration in the WT mice but decreasing it in the KO mice. Finally, patients with MBS history had higher VDR expression in SAT as compared to those without MBS history. ConclusionVDR is necessary for metabolic health after SG in DIO mice due to its role in WAT function, insulin sensitivity and inflammatory response after surgery. Increased expression of VDR in patients post-MBS suggests that it may also contribute to metabolic responses in humans. HighlightsO_LIVDR KO results in delayed glucose utilization following SG in DIO mice C_LIO_LIVDR KO results in progressive loss of improved insulin sensitivity after SG C_LIO_LIVDR KO results in white adipose tissue inflammation and remodeling after SG C_LIO_LIVDR expression increases in human subcutaneous adipose tissue after bariatric surgery C_LI

physiology↗

bioRxiv2022

Sleeve gastrectomy promotes colitis-associated colorectal cancer in a murine model via a modified gut microbiome

Colorectal cancer (CRC) remains the third leading cause of cancer death in the United States with an alarming rise among young (<50-years-old) patients.1 Epidemiologically, obesity appears to be a risk factor for CRC.1 Although bariatric surgery has been shown to be associated with decreased risk for most cancers, studies to date on bariatric surgery and CRC continue to yield conflicting results.2 One possible explanation for this seeming irreconcilability is the inherent heterogeneity of CRC with its varied mechanisms. This is likely compounded by the differing bariatric operations currently employed. Here, we sharpen our focus and investigate how the most performed bariatric operation, sleeve gastrectomy (SG), affects colitis-associated CRC. Using a murine model, we found that SG significantly exacerbates both colitis and colitis-associated CRC. Using a germ-free (GF) microbiota transplant model, we found that the post-SG microbiota, when transplanted into GF mice, is capable of independently recapitulating the tumor-promoting phenotype of SG. Our results suggest that the postsurgical microbiome plays a key causal role in the increased risk for CRC after SG. This finding represents the first step in our understanding of this complex relationship that is at the intersection of two rising public health threats.

cancer biology↗

bioRxiv2021

Daily transient coating of the intestine leads to weight loss and improved glucose tolerance

The worsening obesity epidemic has driven a parallel increase in incidence of type-2 diabetes (T2D) found in 13% of the adult US population. Roux-en-Y gastric bypass surgery (RYGB) is the golden standard surgical treatment for obesity-related T2D. However, over 70% of T2D patient do not meet the NIH criteria for surgery, and many that do, are reluctant to consider such an invasive intervention. Mechanisms behind the antidiabetic effect of RYGB are not clearly understood, but isolation of proximal bowel from nutrient exposure plays a critical role. In this study, we tested the impact of daily administration of an oral gut coating agent, LuCI (Luminal Coating of the Intestine), in controlling weight and insulin resistance. LuCI is not systemically absorbed and provides a transient coating of the proximal intestines and excludes the coated bowel from nutrient contact, thus mimicking the effects of RYGB. We demonstrate that LuCI results in weight loss and improved insulin sensitivity in a rat DIO model. LuCI also appears to replicate hormonal changes seen after RYGB, by increasing post-prandial GLP-1 and GIP levels. LuCI has the potential to replicate the metabolic benefit of surgery and be a novel therapeutic strategy for obesity associated T2D.

bioengineering↗

bioRxiv2021

Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery

Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone. In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

cell biology↗

bioRxiv2020

Weight and organ specific immune cell profiling of Sleeve Gastrectomy

Sleeve gastrectomy (SG) has profound, immediate weight-loss independent effects on obesity related diabetes (T2D). Our prior studies have shown that immunologic remodeling may play a part in this metabolic improvement. However, to date, little is known about how the major immune cell populations change following SG. Using mass cytometry with time of flight analysis (CyTOF) we aimed to broadly explore the organ-specific immune cell repertoire induced by SG. Surgery was performed on obese, insulin resistant and lean mice in order to understand surgery-specific phenotypes. We identified a shift within the splenic B cell compartment with a reduction in follicular and an increase in innate-like B cell subsets in SG animals. There was a concomitant increase in multiple circulating immunoglobulin classes. Further, SG animals had a conserved increase in splenic neutrophils and a tendency toward M2 macrophage polarization. Others have shown that these, weight-loss independent, surgery-specific changes are linked to improved glucose metabolism and thus, may be a major contributor to post SG physiology. Characterizing the complex immune milieu following SG is an important step toward understanding the physiology of SG and the potential therapies therein.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsSG(Sleeve Gastrectomy)(T2D)Type 2 Diabetes(TNF-α)tumor necrosis factor alpha(VAT)visceral adipose tissuePOD(post-operative Day)GLP-1(glucagon like peptide 1)OGTT(oral glucose tolerance test)ITT(insulin tolerance test)DIO(diet induced obesity)CyTOF(cytometry with time of flight analysis)ARG1(arginase 1)TGR5(Takeda g-protein bile acid receptor)RYGB(Roux-en-Y gastric bypass)View Full Text

immunology↗

bioRxiv2020

Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that induces GLP-1 secretion in vitro and in vivo and that CA7S administration increases glucose tolerance in insulin-resistant mice in a GLP-1 receptor-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

biochemistry↗

bioRxiv2019

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

ObjectiveSleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements.\n\nMethodsNon-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis.\n\nResultsIn this model, SG induced durable improvements in glucose tolerance despite not causing lasting changes in weight, fat/lean mass, or food intake. Indirect calorimetry revealed post-SG animals had respiratory exchange ratios (RER) nearing 1.0 on average and had daily RER excursions above 1.0, indicating preferential glucose utilization and increased energy demand, respectively. Sham operated mice demonstrate normal RER feeding/fasting excursions. PET/CT showed increased avidity within white adipose depots. Finally, SG led to an upregulation in the transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation within the visceral adipose tissue.\n\nConclusionsSG induces a rapid, weight-loss independent shift towards glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue.

physiology↗