Publications

Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear.Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity.

Insulin-like peptide 5 (INSL5) signalling, through its cognate receptor relaxin/insulin-like-family-peptide-receptor-4 (RXFP4), has been reported to be orexigenic, and the preference for high fat diet (HFD) observed in wildtype mice is altered in Rxfp4 knock-out mice. In this study, we used a new Rxfp4-Cre mouse model to investigate the mechanisms underlying these observations.We generated transgenic Rxfp4-Cre mice and investigated central expression of Rxfp4 by RT-qPCR, RNAscope and intraparenchymal infusion of INSL5.

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies. Despite this intimate association, the extent to which sympathetic functions are influenced by satellite glia in vivo remains unclear. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons.

How do separate sexes originate and evolve? Plants provide many opportunities to address this question as they have diverse mating systems and separate sexes (dioecy) that evolved many times independently. The classic 'two-factor' model for evolution of separate sexes proposes that males and females can evolve from hermaphrodites via the spread of male and female sterility mutations that turn hermaphrodites into females and males, respectively.

Therapies that promote neuroprotection and axonal survival by enhancing myelin regeneration are an unmet need to prevent disability progression in multiple sclerosis. Numerous potentially beneficial compounds have originated from phenotypic screenings but failed in clinical trials. It is apparent that current cell- and animal-based disease models are poor predictors of positive treatment options, arguing for novel experimental approaches.

Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge is to better understand how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by tumor microenvironment. Here, we show that expression of the cytokine TSLP by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans.

Obesity-induced asthma responds poorly to all current pharmacological interventions, including steroids; suggesting that classic, eosinophilic inflammation is not a mechanism. As insulin resistance and hyperinsulinemia are common in obese individuals and associated with increased risk of asthma, we used diet-induced obese mice to study how insulin induces airway hyperreactivity. Inhaled 5-HT or methacholine induced dose dependent bronchoconstriction that was significantly potentiated in obese mice.

Maternal hyperthyroidism is associated with an increased incidence of congenital abnormalities at birth, but it is not clear which of those defects arise from a transient developmental excess of thyroid hormone, and which depend on pregnancy stage, antithyroid drug choice, or unwanted subsequent fetal hypothyroidism. To address this issue we studied a mouse model of comprehensive developmental thyrotoxicosis secondary to a lack of type 3 deiodinase (DIO3). Dio3-/- mice exhibit reduced neonatal viability on most genetic backgrounds and perinatal lethality on a C57BL/6 background.

Goblet cells in the small intestinal crypts contain large numbers of mucin granules that are rapidly discharged to clean bacteria from the crypt. Because acetylcholine released by neuronal and nonneuronal cells controls many aspects of intestinal epithelial function, we used tissue explants and organoids to investigate the response of the small intestinal crypt to cholinergic stimulation. The activation of muscarinic acetylcholine receptors initiated a coordinated and rapid emptying of crypt goblet cells that flushed the crypt contents into the intestinal lumen.

Based on high-throughput transcriptomic sequencing, SNHG3 was among the most highly expressed long noncoding RNAs in calcific aortic valve disease. SNHG3 upregulation was verified in human and mouse calcified aortic valves. Moreover, in vivo and in vitro studies showed SNHG3 silencing markedly ameliorated aortic valve calcification. In-depth functional assays showed SNHG3 physically interacted with polycomb repressive complex 2 to suppress the H3K27 trimethylation BMP2 locus, which in turn activated BMP2 expression and signaling pathways.