Anatomy and Neuroscience - Research Publications

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    Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
    Montgomery, MK ; Bayliss, J ; Nie, S ; De Nardo, W ; Keenan, SN ; Miotto, PM ; Karimkhanloo, H ; Huang, C ; Schittenhelm, RB ; Don, AS ; Ryan, A ; Williamson, NA ; Ooi, GJ ; Brown, WA ; Burton, PR ; Parker, BL ; Watt, MJ (NATURE PORTFOLIO, 2022-03-10)
    Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.
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    Western Diet Induced Remodelling of the Tongue Proteome
    Dutt, M ; Ng, Y-K ; Molendijk, J ; Karimkhanloo, H ; Liao, L ; Blazev, R ; Montgomery, MK ; Watt, MJ ; Parker, BL (MDPI, 2021-06)
    The tongue is a heavily innervated and vascularized striated muscle that plays an important role in vocalization, swallowing and digestion. The surface of the tongue is lined with papillae which contain gustatory cells expressing various taste receptors. There is growing evidence to suggest that our perceptions of taste and food preference are remodelled following chronic consumption of Western diets rich in carbohydrate and fats. Our sensitivity to taste and also to metabolising Western diets may be a key factor in the rising prevalence of obesity; however, a systems-wide analysis of the tongue is lacking. Here, we defined the proteomic landscape of the mouse tongue and quantified changes following chronic consumption of a chow or Western diet enriched in lipid, fructose and cholesterol for 7 months. We observed a dramatic remodelling of the tongue proteome including proteins that regulate fatty acid and mitochondrial metabolism. Furthermore, the expressions of several receptors, metabolic enzymes and hormones were differentially regulated, and are likely to provide novel therapeutic targets to alter taste perception and food preference to combat obesity.
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    Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease
    Watt, K ; Henstridge, DC ; Ziemann, M ; Sim, CB ; Montgomery, MK ; Samocha-Bonet, D ; Parker, BL ; Dodd, GT ; Bond, ST ; Salmi, TM ; Lee, RS ; Thomson, RE ; Hagg, A ; Davey, JR ; Qian, H ; Koopman, R ; El-Osta, A ; Greenfield, JR ; Watt, MJ ; Febbraio, MA ; Drew, BG ; Cox, AG ; Porrello, ER ; Harvey, KF ; Gregorevic, P (NATURE RESEARCH, 2021-05-17)
    Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.