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 applicant to receive additional training in brown
adipose biology, neuronal regulation of browning activity, proteomics based secreting factor identification, and
therapeutic discovery, thereby fully supporting a successful transition to independence for the applicant.