Biology subjects

Sandoval, D. A.

Publications and source records attributed to Sandoval, D. A..

3 recordsLinked to original sources

bioRxiv2021

Vertical Sleeve Gastrectomy Induces Enteroendocrine Cell Differentiation of Intestinal Stem Cells Through Farnesoid X Receptor Activation

Vertical sleeve gastrectomy (VSG) is one of several bariatric procedures that substantially improves glycemia and energy homeostasis. Increased secretion of multiple gut peptides has been hypothesized to be a critical contributor to VSGs potent effects to reduce body weight and improve glucose regulation. VSG results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium, but whether this increase is via proliferation or differentiation of EECs and their subtypes remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the bile acid nuclear receptor, farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models, but whether it plays a role specifically in normal intestinal differentiation remains unknown. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express eGFP in ISC/progenitor cells and performed RNAseq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by GLP-1) in mouse intestinal organoids following treatment with bile acids and/or an FXR antagonist. RNA-seq revealed that FXR is expressed in ISCs and that VSG explicitly alters ISC expression of several genes that regulate intestinal secretory cell development, including EEC differentiation. Mouse intestinal organoids treated with bile acids increased GLP-1-positive cell numbers, whereas a potent FXR antagonist blocked this effect. Taken together, these data indicate that VSG drives ISC fate towards EEC differentiation through FXR signaling.

physiology↗

bioRxiv2020

Intestinal-derived FGF15 preserves muscle and bone mass following sleeve gastrectomy

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive, but provide the most effective long-term metabolic improvements in obese and Type 2 diabetic patients. These powerful effects of manipulating the gastrointestinal tract point to an important role of gastrointestinal signals in regulating both energy balance and metabolism. To that end, we have used mouse models of VSG to identify key gut signals that mediate these beneficial effects. Preliminary data from our rodent model of VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal enterocytes of the small intestine and is released postprandially. Like many other gut hormones, postprandial plasma levels in humans and ileal FGF15 expression in mice increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2; Fgf15f/f) mice and controls, which were maintained on 60% high-fat diet. Interestingly, ablation of intestinal FGF15 in adult mice results in little change to body weight or glucose regulation when challenged with a high-fat diet. Unlike what we had predicted, intestinal-specific FGF15 knock out mice lost more weight after VSG and this was a result of increased lean tissue loss compared to control mice. Further, the loss of bone mineral density observed after VSG in control mice was increased in intestinal-specific FGF15 knock out mice. Finally the effect of VSG to reduce hepatic cholesterol was also absent in intestinal-specific FGF15 knock out mice. These data point to an important role for intestinal FGF15 to protect the organism from deleterious effects of rapid weight loss that occurs after VSG.Competing Interest StatementRJS has received research support from Ethicon Endo-Surgery, Zafgen, Novo Nordisk, Kallyope, and MedImmune. RJS has served on scientific advisory boards for Ethicon Endo-Surgery, Novo Nordisk, Sanofi, Janssen, Kallyope, Scohia, and Ironwood Pharma. RJS is a stakeholder of Zafgen. KMH is a paid-employee of Novo Nordisk.View Full Text

physiology↗

bioRxiv2020

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

Obesity and type 2 diabetes mellitus (T2D) are growing epidemics resulting in increased morbidity and mortality. An emerging body of evidence has shown that elevated levels of branched-chain amino acids (BCAA) and their metabolites are strongly positively associated with obesity, insulin-resistance and T2D. Bariatric surgery is among the best treatments for weight loss and the alleviation of T2D. Additionally, clinical studies have reported that bariatric surgery decreases the circulating levels of BCAA. The objective of these studies was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements after VSG. We find that, as in humans, circulating BCAA levels are significantly lower in VSG rats and mice compared to Sham controls. In order to increase circulating BCAA levels, we tested mice with either increased dietary intake of BCAA or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C, Pp2cm, a key enzyme in the rate-limiting step in BCAA catabolism. Our results show that a decrease in circulating BCAA levels is not necessary for sustained body weight loss and improved glucose tolerance after VSG. While it is clear that circulating levels of BCAAs are excellent biomarkers for metabolic status, the current data do not support a causal role in determining metabolic regulation and the response to VSG.

physiology↗