Project Summary/Abstract One third of American adults are suffering from obesity, which significantly contributes to the prevalence of many other life-threatening diseases, such as type 2 diabetes, cardiovascular diseases, cancers, etc. Although substantial resources have been deployed to resolve this major public health threat, the fact is that currently only limited ways of intervention have been developed. An in-depth understanding of the pathogenesis of obesity to facilitate finding more effective therapeutics is urgently needed. The overarching goal of this K01 proposal is to investigate the crosstalk between two major players in the onset of obesity, white and brown adipose tissues, and to identify novel factors mediating the white fat-brown fat communication. The applicant recently has identified that overexpression of amyloid precursor protein (APP) in white fat and its subsequent mistargeting into mitochondria induces dramatic mitochondrial dysfunction, thereby promoting obesity and insulin resistance. Preliminary data obtained from this unique APP-induced mitochondrial distress model show that mitochondrial distress in white fat induces a “whitening” phenotype in brown fat, and in contrast, brown fat- specific mitochondrial distress causes “browning” in white fat. Therefore, this proposal is set out to test the central hypotheses: 1) APP-induced mitochondrial distress is a central determinant of white/brown fat intercommunication; 2) white/brown fat intercommunication involves yet unrecognized signals; 3) white/brown fat intercommunication impacts systemic metabolism. In Aim 1, white or brown fat-specific overexpression or deletion of APP mouse models will be subject to metabolic characterizations and mechanistic investigations. In Aim 2, multiple layers of unbiased strategies will be conducted to discover neuronal or hormonal factors that act as communicating signals between white and brown fat, and these factors are predicted to exert important obesogenic or anti-obesogenic roles. Meanwhile, as a career development award, this proposal also outlines an integrated training and research plan for the applicant to complete further academic training under the mentorship of Dr. Philipp E. Scherer and Dr. Joel K. Elmquist, ensuing the transition to an independent investigator specializing in the field of metabolically active tissue crosstalk in the context of obesity. Furthermore, the outstanding resources provided by UT Southwestern Medical Center will maximize the potential for the applicant to fulfill the career objectives in identifying novel mechanisms underlying pathogenesis of obesity and new therapeutics treating obesity. Combined, together with longstanding interest and established ability of the applicant in studying adipose tissue biology, excellent mentorship from internationally recognized leaders in the metabolism field, and unparalleled environment at UT Southwestern, this K01 career development award will be essential for the...