Assessment of the role of FGF15 in mediating the metabolic outcomes of murine Vertical Sleeve Gastrectomy (VSG).

Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its co-morbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in human and its murine orthologue Fgf15 plays a pivotal role in this bile acid driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15 deficient mice. 6-8 weeks old male wildtype mice (WT) and Fgf15 deficient mice (KO) were fed a high fat diet (HFD) for 8 weeks. At 8th week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Post-surgery, mice were observed for 8 weeks while fed a HFD and then euthanized to collect tissues for experimental analysis. Fgf15 deficient (KO) mice lost weight post VSG, but glucose tolerance in KO mice did not improve post VSG compared to WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post VSG both WT and KO mice had similarly altered bile acid enterohepatic flux, however Fgf15 deficient mice post VSG had increased hepatic accumulation of free and esterified cholesterol leading to lipotoxicity related ER stress, inflammasome activation, and increased Fgf21 expression. Intact Fgf15 mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared to their canonical downstream signaling pathways.

A convenient approach to facilitate monitoring Gaucher disease progression and therapeutic response.

Gaucher disease (GD) is caused by mutations on the GBA1 gene leading to deficiency in acid ß-glucosidase (GCase) and subsequent accumulation of its substrates, glucosylceramide (GlcC) and glucosylsphingosine (GlcS). GlcS in plasma has been proposed as a highly sensitive and specific biomarker for the diagnosis of GD and for monitoring disease progression and response to therapy. Here we report a novel robust and accurate hydrophilic interaction liquid chromatography tandem mass spectrometric method (HILIC-MS/MS) for the direct measurement of glucosylsphingosine (GlcS) in dried plasma spots (DPS). The method was also capable of resolving the isomeric pair, glucosylsphingosine and galactosylsphingosine, the latter of which was proposed as a promising biomarker for Krabbe disease. The method was fully validated and applied to the analysis of 19 GD patients and carriers. The GlcS levels in 9 GD type I patients who have been on enzyme replacement therapy (ERT) were reduced to a mean of 31.0 nM, much lower compared to a pre-treated specimen at a level of 85.8 nM, but still significantly elevated compared to healthy controls. GlcS concentrations in three treated type III GD patients were much lower compared to an untreated patient. In our preclinical GD studies, 4L;C* mice (subacute nGD model) exhibited comparable levels of plasma GlcS, but had much higher GlcS accumulation in the brain than those of 9V/null mice (chronic neuropathic GD model). Our method for the measurement of GlcS in DPS proved to be a very convenient approach for sample collection, storage and shipping nationwide and internationally.

Fibroblast growth factor 21 correlates with weight loss after vertical sleeve gastrectomy in adolescents.

OBJECTIVE: Vertical sleeve gastrectomy (VSG) results in weight loss and increased bile acids (BA) and fibroblast growth factor 19 (FGF19) levels. FGF21 shares essential cofactors with FGF19, but its physiology early post-VSG has not been assessed. METHODS: Ten adolescents (17.4 ± 0.5 years and BMI 51.5 ± 2.5 kg/m2 ) were enrolled. Fasting and postmeal (100 mL Ensure™) samples (0-120 min) were collected (pre-VSG [V1], 1 [V2], and 3 months [V3] post-VSG) for analysis of BA, FGF19, and FGF21. RESULTS: Post-VSG subjects lost weight (V2 11.8 ± 0.8 kg; V3 21.9 ± 1.7 kg). BA and FGF19 increased by V2, 143.6% at 30 min and 74.9% at 90 min post-meal, respectively. BA hydrophobicity index also improved by V3, 21.1% at 30 min post-meal. Interestingly, fasting and 120-min post-meal FGF21 levels at V2 were increased by 135.7% and 253.9%, respectively, but then returned to baseline at V3. BA levels correlated with FGF21 at V2 (P = 0.003, r = 0.89), and body weight lost post-VSG correlated with FGF21 levels (V2; P = 0.012, R = 0.82). CONCLUSIONS: Expected changes were seen in BA and FGF19 biology after VSG in adolescents, but novel changes were seen in correlation between the early postsurgical increase in FGF21 and weight loss, suggesting that FGF21 may play a role in energy balance postoperatively, and further investigation is warranted.

Bile Acid Signaling: Mechanism for Bariatric Surgery, Cure for NASH?

Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease--nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precursor to the development of liver cirrhosis that may necessitate liver transplantation in the long run. Simultaneously, we and others have observed increased serum bile acids in humans and animals that undergo bariatric surgery. Specifically, our preclinical studies have included experimental procedures such as 'ileal transposition' or bile diversion and established procedures such as Roux-en-Y gastric bypass and the adjustable gastric band. Importantly, these effects are not simply the result of weight loss since our data show that the resolution of NASH and increase in serum bile acids are not seen in rodents that lose an equivalent amount of weight via food restriction. In particular, we have studied the role of altered bile acid signaling, in the potent impact of a bariatric procedure termed 'vertical sleeve gastrectomy' (VSG). In this review we focus on the mechanisms of NASH resolution and weight loss after VSG surgery. We highlight the fact that bariatric surgeries can be used as 'laboratories' to dissect the mechanisms by which these procedures work to improve obesity and fatty liver disease. We describe key bile acid signaling elements that may provide potential therapeutic targets for 'bariatric-mimetic technologies' that could produce benefits similar to bariatric surgery--but without the surgery!