The role of the TWEAK/Fn14 signaling pathway in the metabolic and inflammatory response to diet-induced obesity.
tissue (AT) expansion requires a program of active tissue remodeling involving
temporally-orchestrated patterns of inflammatory cell recruitment, extracellular matrix
(ECM) degradation and collagen turnover that promotes adipocyte hypertrophy,
adipogenesis and neovascularization. It is now appreciated that these processes become
dysregulated in chronic obesity, resulting in ... read moreunresolved, maladaptive tissue remodeling
that contributes to AT inflammation and metabolic complications of obesity, including
dyslipidemia and insulin resistance (IR). Identifying and exploiting therapeutic targets
that regulate these processes may be effective ways of mitigating the metabolic
complications of obesity. Tumor necrosis factor-related weak inducer of apoptosis
(TWEAK) is a cytokine of the tumor necrosis factor (TNF) superfamily that is involved in
tissue repair and wound healing. Engagement of TWEAK with its exclusive signaling
receptor, fibroblast growth factor-inducible gene 14 (Fn14) activates NF κB and
MAPK inflammatory signaling pathways that regulate expression of tissue remodeling genes
called matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Recent studies and
data herein demonstrate that TWEAK and Fn14 gene expression are upregulated in AT of
obese humans and mice. Therefore, our objective was to determine the role of TNF-like
weak inducer of apoptosis (TWEAK) in the regulation of AT mass and architecture as well
as glucose/insulin homeostasis in obesity. The ultimate goal of this work was to
determine if targeting TWEAK / Fn14 signaling would be a viable strategy for promoting
metabolic health in obesity. Research Design and Methods: Male TWEAK knock-out (KO) and
wildtype (WT) mice (9-12 weeks old) were fed a normal diet (ND; 17% kcal from fat) or
high fat diet (HFD; 60% kcal from fat) for 17 weeks. Energy metabolism, body
composition, and glucose and insulin tolerance were measured. Tissues were analyzed by
QPCR, FACS, Western blotting, ELISA, histology and biochemical assays. Results: In WT
mice, TWEAK and Fn14 were upregulated by HFD in gonadal AT (gAT) but not other AT
depots. Relative to WT mice, HFD-fed KO mice had >30% larger gAT depots, reflecting
adipocyte hypertrophy. Obese KO mice were insulin sensitive and more glucose tolerant
than WT, and had increased insulin-stimulated Akt activation concomitantly with
significantly lower levels of circulating triglyceride and non-esterified fatty acids
and decreased triglycerides in liver and quadriceps. No differences in energy metabolism
were detected between genotypes. Genes involved in tissue remodeling (Interleukin-13,
Chitinase 3-like 3) were upregulated in gAT of obese KO mice in association with an
expression profile of MMPs and TIMPs that was consistent with adipocyte hypertrophy and
gAT expansion (elevated MMP-14/TIMP-2 ratio, diminished MMP-3/TIMP-1 ratio).
Accordingly, there was an increased proportion of newly synthesized collagen I fibrils
and a decreased proportion of mature collagen I fibers in gAT of obese KO mice with
attenuated stress kinase activation. Conclusion and Implications: Here we demonstrate
that TWEAK promotes pathologic gAT remodeling, thereby contributing to the fibrotic and
inflammatory gAT phenotype and metabolic complications of chronic obesity. By using an
animal model in which TWEAK is genetically ablated, we were the first to test this
hypothesis in vivo. The results presented herein imply that this pathway is a potential
target for promoting metabolic health in obesity and warrants further
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Martin Obin.
Committee: Linda Burkly, Andrew Greenberg, and Dayong Wu.
Keyword: Nutrition.read less