Tgr5-/- mice are protected from ethanol-induced metabolic alterations through enhanced leptin and Fgf21 signaling.

BACKGROUND: Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury. METHODS: Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways. RESULTS: Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet. CONCLUSIONS: Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer's Disease Mice.

BACKGROUND: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer's disease (AD) and may coincide with early accumulation of amyloid-ß (Aß) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aß imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. OBJECTIVE: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cells (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. METHODS: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aß levels were assessed with advanced protein quantitation techniques. RESULTS: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. CONCLUSION: These data support the premise that retinal Aß is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.

Mechanistic complexities of bone loss in Alzheimer's disease: a review.

Purpose/Aim: Alzheimer's disease (AD), the primary cause of dementia in the elderly, is one of the leading age-related neurodegenerative diseases worldwide. While AD is notorious for destroying memory and cognition, dementia patients also experience greater incidence of bone loss and skeletal fracture than age-matched neurotypical individuals, greatly impacting their quality of life. Despite the significance of this comorbidity, there is no solid understanding of the mechanisms driving early bone loss in AD. Here, we review studies that have evaluated many of the obvious risk factors shared by dementia and osteoporosis, and illuminate emerging work investigating covert pathophysiological mechanisms shared between the disorders that may have potential as new risk biomarkers or therapeutic targets in AD.Conclusions: Skeletal deficits emerge very early in clinical Alzheimer's progression, and cannot be explained by coincident factors such as aging, female sex, mobility status, falls, or genetics. While research in this area is still in its infancy, studies implicate several potential mechanisms in disrupting skeletal homeostasis that include direct effects of amyloid-beta pathology on bone cells, neurofibrillary tau-induced damage to neural centers regulating skeletal remodeling, and/or systemic Wnt/Beta-catenin signaling deficits. Data from an increasing number of studies substantiate a role for the newly discovered "exercise hormone" irisin and its protein precursor FNDC5 in bone loss and AD-associated neurodegeneration. We conclude that the current status of research on bone loss in AD is insufficient and merits critical attention because this work could uncover novel diagnostic and therapeutic opportunities desperately needed to address AD.