My team aims to understand the role of the CNS in regulating body weight and glucose homeostasis. We investigate molecular mechanisms residing in the hypothalamus that drive Yoyo dieting and our failure to stay lean. For instance, we revealed a novel role for histone deacetylase 5 as hypothalamic regulator of body weight and leptin signaling (1). We further assessed leptin blood brain barrier transport (2) and the leptin sensitizing properties of the plant-derived small molecule celastrol (3,4). Recently, major efforts in the lab shifted toward identifying novel epigenetic regulators of weight cycling. We spent considerable time and efforts to establish methods and tools such as FACS sorting of neuronal nuclei and low input RNAseq or HT-ChIPmentation followed by the appropriate bioinformatic analyses which are currently applied to brains of murine models of obesity, Yoyo dieting and weight-loss induced by either bariatric surgery, calorie restriction or pharmacological intervention with exendin-4 (Ex-4).
Bioinformatical and CRISPR-Cas9-guided identification of hypothalamic anti-obesity targets
While conducting these murine weight loss studies, we observed that weight-loss induced by bariatric surgery or Ex-4 treatment is superior to weight loss induced by calorie restriction. Reasons for this discrepancy remain largely elusive, but profound differences in the hypothalamic transcriptome and proteome (total, phospho) profiles of the weight-loss groups point towards the hypothalamus as the affected regulatory center. These new Omics datasets now await further analysis. Specifically, we aim to identify targets and molecular mechanisms that explain the benefits of bariatric surgery and pharmacology over calorie restriction. We are looking for a motivated experimental biologist that is willing to utilize a wide range of techniques and approaches for his/her work. The candidate will gain basic expertise in R- or Python-based data analysis by interacting closely with our team of bioinformaticians and by attending workshops and classes. Previous knowledge is not required. The PhD candidate is further expected to use cellular and murine CRISPR-Cas9/dCas9 models for gain- or loss-of- function studies combined with state-of-the-art methodology to assess the physiological relevance of known and future candidate target genes. In a mandatory 6-months-stay at the lab of Prof. Jessica Yue, University of Alberta, Edmonton, Canada, the candidate will investigate the impact of the different weight-loss regiments on the CNS control of autonomic nervous system function and hepatic glucose and lipid metabolism.
1. Kabra DG et al. Hypothalamic leptin action is mediated by histone deacetylase 5. Nat Commun. 2016 Feb29;7(1):10782.
2. Harrison L et al. Fluorescent blood-brain barrier tracing shows intact leptin transport in obese mice. Int J Obes (Lond). 2019 Jun;43(6):1305–18.
3. Pfuhlmann K et al. Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1. Diabetes. 2018 Nov;67(11):2456–65.
4. Kyriakou E et al. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. J Med Chem. 2018 Dec 27;61(24):11144–57.
5. Kirchner H et al. Caloric restriction chronically impairs metabolic programming in mice. Diabetes. 2012 Nov;61(11):2734–42.
6. Müller TD et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J Pept Sci. 2012 Jun;18(6):383–93.