Intestinal FFA2 promotes obesity by altering food intake in Western diet-fed mice.

Short-chain fatty acids (SCFAs) are key nutrients that play a diverse set of roles in physiological function, including regulating metabolic homeostasis. Generated through the fermentation of dietary fibers in the distal colon by the gut microbiome, SCFAs and their effects are partially mediated by their cognate receptors, including free fatty acid receptor 2 (FFA2). FFA2 is highly expressed in the intestinal epithelial cells, where its putative functions are controversial, with numerous in vivo studies relying on global knockout mouse models to characterize intestine-specific roles of the receptor. Here, we used the Villin-Cre mouse line to generate a novel, intestine-specific knockout mouse model for FFA2 (Vil-FFA2) to investigate receptor function within the intestine. Because dietary changes are known to affect the composition of the gut microbiome, and can thereby alter SCFA production, we performed an obesogenic challenge on male Vil-FFA2 mice and their littermate controls (FFA2-floxed, FFA2fl/fl) to identify physiological changes on a high-fat, high-sugar 'Western diet' (WD) compared to a low-fat control diet (CD). We found that the WD-fed Vil-FFA2 mice were transiently protected from the obesogenic effects of the WD and had lower fat mass and improved glucose homeostasis compared to the WD-fed FFA2fl/fl control group during the first half of the study. Additionally, major differences in respiratory exchange ratio and energy expenditure were observed in the WD-fed Vil-FFA2 mice, and food intake was found to be significantly reduced at multiple points in the study. Taken together, this study uncovers a novel role of intestinal FFA2 in mediating the development of obesity.

Orthostatic hypotension as the initial presentation of disseminated cryptococcosis in a kidney transplant recipient.

Background: Solid organ transplant recipients are immunocompromised and at risk for invasive viral, fungal, and bacterial pathogens. Cryptococcus neoformans is the third most common invasive fungal infection in transplant recipients, and the clinical presentation of Cryptococcus neoformans infection can vary widely. Cryptococcal disease can affect the brain, lungs, skin, or vasculature, and it is frequently disseminated. Meningitis typically presents with fever, headache, and altered mental status. Solid organ transplant recipients with cryptococcosis tend to have poorer outcomes than HIV patients with cryptococcosis. Case presentation: In this case report, we describe the case of a 69 year-old man with a past medical history of a deceased donor kidney transplant who presented with severe orthostatic hypotension and was found to have disseminated cryptococcosis. Conclusions: This case report emphasizes the importance of broadening the differential diagnosis in transplant recipients who present with non-specific chief concerns. Availability of data and materials: No datasets were used in the preparing of this manuscript. All patient information comes from the electronic health record and authors personal care of this patient.

Intestinal FFA3 mediates obesogenic effects in mice on a Western diet.

Free fatty acid receptor 3 (FFA3) is a recently-deorphanized G-protein-coupled receptor. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients derived from the gut microbiome fermentation process that play diverse roles in the regulation of metabolic homeostasis and glycemic control. FFA3 is highly expressed within the intestine, where its role and its effects on physiology and metabolism are unclear. Previous in vivo studies involving this receptor have relied on global knockout mouse models, making it difficult to isolate intestine-specific roles of FFA3. To overcome this challenge, we generated an intestine-specific knockout mouse model for FFA3, Villin-Cre-FFA3 (Vil-FFA3). Model validation and general metabolic assessment of male mice fed a standard chow diet revealed no major congenital defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, an obesogenic challenge was performed on male Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "Western diet" (WD) compared with a low-fat control diet (CD). Vil-FFA3 mice versus FFA3fl/fl controls on WD, but not CD, were protected from the development of diet-induced obesity and exhibited significantly less fat mass as well as smaller adipose depositions and adipocytes. Although overall glycemic control was unchanged in the WD-fed Vil-FFA3 group, fasted glucose levels trended lower. Intestinal inflammation was significantly reduced in the WD-fed Vil-FFA3 mice, supporting protection from obesogenic effects. Furthermore, we observed lower levels of gastric inhibitory protein (GIP) in the WD-fed Vil-FFA3 mice, which may contribute to phenotypic changes. Our findings suggest a novel role of intestinal FFA3 in promoting the metabolic consequences of a WD, including the development of obesity and inflammation. Moreover, these data support an intestine-specific role of FFA3 in whole body metabolic homeostasis and in the development of adiposity.NEW & NOTEWORTHY Here, we generated a novel intestine-specific knockout mouse model for FFA3 (Vil-FFA3) and performed a comprehensive metabolic characterization of mice in response to an obesogenic challenge. We found that Vil-FFA3 mice fed with a Western diet were largely protected from obesity, exhibiting significantly lower levels of fat mass, lower intestinal inflammation, and altered expression of intestinal incretin hormones. Results support an important role of intestinal FFA3 in contributing to metabolism and in the development of diet-induced obesity.

FFAR from the Gut Microbiome Crowd: SCFA Receptors in T1D Pathology.

The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders.

Effects of transvenous pacing on cardiac troponin release.

Cardiac troponins are invaluable tools for the detection of minimal myocardial injury. No study to date has analyzed the effect of permanent cardiac pacing on minimal myocardial injury detection by cardiac troponin I (cTnI) measurement. We investigated 76 clinically stable patients (mean age 75 years, range 31-93 years, 59% men) listed for elective endocardial permanent pacemaker insertion. Patients were required to have normal levels of cardiac cTnI, aspartate transaminase (AST) and creatinine kinase (CK) on a venous blood sample taken immediately prior to elective pacemaker implantation. Repeat measurements of AST, CK, and cTnI were performed at a mean of 19.2 post implantation. There was a detectable small rise in cTnI levels above normal in 21% of patients in a second blood sample taken 18-21 hours later (mean cTnI 0.39 +/- 0.37 microg/L, normal < 0.15 microg/L). The only factor that correlated with this rise was prolonged x ray screening time for lead implantation.