Novel Mechanisms Regulating the Adipocyte-Brain-Hepatocyte Axis

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 DESCRIPTION (provided by applicant): The central integration of peripheral metabolic cues that lead to the coordinated control of liver and adipose tissue metabolism is very important, yet not well understood. Thus, we propose a set of projects that revolve around the general theme of sensing of peripheral metabolites, such as LIPIDS and URIDINE. A team of experienced investigators has coalesced at UT Southwestern that includes Phil Scherer, an expert in the area of adipocyte-derived factors, Joel Elmquist, an authority on central regulation of energy homeostasis and Jay Horton, bridging the CNS and adipose tissue through his studies on hepatic lipid metabolism. This team looks back on 5 years of successful collaborative efforts under the ongoing Program Project, together with our Core Directors Syann Lee and Ruth Gordillo. Project 1 (Scherer) will focus on the consequences of manipulating the cellular uridine biosynthesis in the adipocyte and hepatocyte by eliminating and overexpressing the key enzymatic machinery for uridine production. This is highly relevant in light of the important metabolic adaptations to the feeding/fasting cycle between the liver (Horton) and adipocytes (Scherer), governed primarily by the transcription factor Xbp1s that also exerts important functions in the brain (Elmquist). A detailed assessment will be performed on the impact of the fasting-induced plasma uridine increase on leptin signaling (Elmquist) and studies on the involvement of Toll-like receptor 4 and CD36 on the activation of Xbp1s in multiple tissues will be performed (Elmquist, Horton, Scherer). Project 2 (Elmquist) will examine in detail whether fatty acid uptake or synthesis in vagal sensory neurons regulates energy balance and glucose homeostasis in the liver (Horton) and the adipocyte (Scherer) by manipulating CD36 and ACC1 levels, thereby lowering local malonyl-CoA levels. In a complementary approach leading to an upregulation of malonyl-CoA through deletion of fatty acid synthase (FAS) in POMC and/or AgRP neurons, Elmquist will probe the impact on browning of white adipose tissue (with Scherer) and hepatic insulin sensitivity (with Horton). Project 3 (Horton) focuses on lipotoxic signals derived from livers and/or adipocytes in the context of the AGPAT2 null mouse. These mice serve as an excellent model system for congenital lipodystrophy, mirroring the clinical manifestations of AGPAT2 deficiency, such as insulin resistance, NAFLD, and lipodystrophy. Horton will focus on novel, non-conventional transcriptional activators of lipogenesis that are at play in this model, and specifically test whether the prominent ceramide accumulation observed in this model is responsible for the metabolic dysregulation. He will also carefully dissect the relative contributions of liver versus adipocyte AGPAT2 activity through inducible gain- and loss of function models in close collaboration with Scherer. Our strengths rely on the diverse expertise of the project leaders, the systematic sharing of animal models and the tightly interwoven thematic approaches amongst the three projects.