The central integration of peripheral metabolic cues that lead to coordinated control of liver metabolism is very important, yet not well understood. Thus, we propose a set of projects that revolve around the general theme of peripheral inflammatory factors, such as adipokines, dietary lipids, and sex steroids, engaging key sites in the brain. These factors relay signals through autonomic and neuroendocrine outputs, thereby regulating liver function. Recently, 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 Deborah Clegg, bridging the CNS and adipose tissue through her studies on sex hormone regulation of obesity through modulation of inflammatory pathways. This group is complemented by the contributions of David Mangelsdorf who will closely collaborate with Joel Elmquist and will also direct a Nuclear Receptor Profiling Core that will be critical for all of the mouse models we will be producing in our studies. Joyce Repa, who will be collaborating with Phil Scherer on defining the differential transcriptional control of lipogenic pathways in adipocytes and vagal sensory neurons and Jay Horton who will direct the Metabolic Phenotyping Core. Project 1 (Scherer/Repa) will focus on the consequences of activation or inactivation of key pro-inflammatory pathways induced in adipocytes by external lipid-mediated events (via TLR4/ NFKB) on local and central mechanisms affected by altered lipid and adipokine levels. We will also take advantage of a novel function of the ER stress marker Xbp1s that allows us to potently suppress lipogenesis in an inducible fashion in both adipocytes and nodose ganglia neurons to probe the effects of lowering endogenously produced lipid pools on local inflammation. Project 2 (Elmquist/Mangelsdorf) will focus on vagal afferent neurons in the nodose ganglia that are ideally positioned to serve as a link between peripheral metabolic and inflammatory signals and the neural pathways controlling hepatic and whole body glucose homeostasis. Local PPARy, LXRo/p and TLR4/NFKBmediated events in the nodose ganglia will be probed for effects on hepatic and whole body glucose homeostasis. Project 3 (Clegg/Fukuda) will focus on the anti-inflammatory properties that the estrogen receptor ERa exerts peripherally in adipocytes and centrally in POMC -positive neurons. Our strengths rely on the diverse expertise of the project leaders and the systematic sharing of animal models and of state-of-the- art methodologies. Combined, we feel we are uniquely positioned to address these questions that tie at the core of homeostatic control of energy homeostasis.
We do not understand how peripheral tissues, such as adipose tissue, convey metabolic signals to the CNS, and how these signals are communicated back to periphery, such as the liver. Here, we propose to examine the specific role of inflammatory signals in this process by focusing on pro- and anti-inflammatory actions of several proteins in adipose tissue and within the CNS, such as the hypothalamus and the vagal afferent neurons in the nodose ganglia. As such, the proposed studies should shed light on an important (neuro)endocrine loop that remains vastly unexplored.
|Sun, Kai; Park, Jiyoung; Kim, Min et al. (2017) Endotrophin, a multifaceted player in metabolic dysregulation and cancer progression, is a predictive biomarker for the response to PPAR? agonist treatment. Diabetologia 60:24-29|
|Rutkowski, Joseph M; Pastor, Johanne; Sun, Kai et al. (2017) Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney Int 91:324-337|
|Udit, Swalpa; Burton, Michael; Rutkowski, Joseph M et al. (2017) Nav1.8 neurons are involved in limiting acute phase responses to dietary fat. Mol Metab 6:1081-1091|
|Tanowitz, Herbert B; Scherer, Philipp E; Mota, Maria M et al. (2017) Adipose Tissue: A Safe Haven for Parasites? Trends Parasitol 33:276-284|
|Holland, William L; Xia, Jonathan Y; Johnson, Joshua A et al. (2017) Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis. Mol Metab 6:267-275|
|Ghaben, Alexandra L; Scherer, Philipp E (2017) Pas de Deux: Glucagon and Thyroid Hormone Moving in Perfect Synchrony. Circ Res 120:762-764|
|An, Yu A; Sun, Kai; Joffin, Nolwenn et al. (2017) Angiopoietin-2 in white adipose tissue improves metabolic homeostasis through enhanced angiogenesis. Elife 6:|
|Deng, Yingfeng; Wang, Zhao V; Gordillo, Ruth et al. (2017) An adipo-biliary-uridine axis that regulates energy homeostasis. Science 355:|
|Dufurrena, Quinn; Amjad, Farhad M; Scherer, Philipp E et al. (2017) Alterations in pancreatic ? cell function and Trypanosoma cruzi infection: evidence from human and animal studies. Parasitol Res 116:827-838|
|Xu, Yong; O'Malley, Bert W; Elmquist, Joel K (2017) Brain nuclear receptors and body weight regulation. J Clin Invest 127:1172-1180|
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