The role of growth factors in white fat browning and metabolic disease

The adipose tissue is composed of a variety of cell types that constantly cross-communicate with each other to allow the tissue to operate and to adapt to various external stimuli. The diversity of these cell populations and their production of secretory factors define not only adipose tissue morphology, but also its function. This regulatory network is particularly important in times of adipose tissue remodeling and failure to adapt may result in severe malfunction of adipose tissues. Data presented in this thesis provide evidence that stromal vascular cells of the adipose tissue have important functions in adipose tissue remodeling and metabolic activation. We specifically focus on the role of various tyrosine kinase growth factor families such as VEGF, PDGF and FGF and their capacity to alter the adipose tissue microenvironment by their ability to remodel blood vessels or promote differentiation of vessel-associated cells into adipocytes.

In paper I, we identified a miRNA-327-FGF10-FGFR2 autocrine regulatory loop that is fundamental for white adipocyte browning. We provide the first evidence that a miRNA-dependent mechanism can control the differentiation of PDGFR-αP+P cells into thermogenic beige cells. We further demonstrated that FGF10 is not only important for white adipocyte differentiation, but additionally possesses the ability to recruit and activate beige adipocytes. Finally, systemic inhibition of miRNA-327 induced white adipocyte browning, thereby improving whole-body metabolic rates and norepinephrine-induced thermogenesis in an FGF10 dependent manner. Our data suggest a therapeutic potential of FGF10 modulating miRNAs for treatment of obesity and related metabolic diseases.

Paper II represents a detailed characterization of the function of VEGFR1 in the adipose tissue during browning and brown adipose tissue activation. Since VEGFR1 acts as a decoy receptor for VEGF, loss of VEGFR1 results in an increase of VEGF-VEGFR2 complex formation and thereby robust angiogenesis. The generation of two distinct endothelial cell specific knockout mouse strains allowed us to demonstrate that loss of VEGFR1 in endothelial cells is sufficient to induce adipose tissue angiogenesis and thereby white adipocyte browning and brown adipose tissue activation. Loss of VEGFR1 in adipocytes or myeloid cells, however, had no detectable effect on adipose tissues. Endothelial specific VEGFR1 KO mice were resistant to diet-induced obesity, resulting in improved insulin sensitivity and a reduction of ectopic lipid accumulation in the liver. Therefore, VEGFR1 blockade in endothelial cells represents an attractive approach to treat obesity, type 2 diabetes and liver steatosis.

In paper III we demonstrate that angiogenic endothelial cells produce PDGF-CC, which results in white adipose tissue browning. We show that such white adipose tissue browning can be prevented by: 1) inhibition of angiogenesis by VEGFR2 blockade, 2) systemic knockout of Pdgfc, or 3) by treatment with a PDGFR-α neutralizing antibody; all resulted in the inability of WAT to undertake a beige phenotype. We could demonstrate that endothelial cells influence adipocyte function in a paracrine fashion by secreting PDGF-CC that drives PDGFR-αP+P preadipocytes into beige adipocyte differentiation. Hence, we conclude that an increase in PDGF-CC levels or the activation of PDGFR-α downstream signaling in preadipocytes might be a novel treatment options for obese patients.

In paper IV we asked the question why age is such a strong indicator for obesity and insulin resistance, and if blood vessels play a role. We produced evidence that continuous age-related changes in the adipose vasculature modulate fat mass, adipocyte function, insulin sensitivity and blood lipid profiles. In middle-aged mice, blood vessel numbers were low and VEGFR1 expression levels high, resulting in reduced vascular plasticity. Surprisingly, middle-aged mice on high-fat diet, but not standard chow, are highly sensitive to anti-VEGF treatment, which resulted in reduced body weight, improved HOMA-IR and enhanced glucose clearance. These findings indicate that low vascular plasticity in middle-aged individuals increases their risk to suffer from obesity and type-2 diabetes.

Collectively, this thesis work uncovers important players in the cross talk between the adipose tissue vasculature and adipocytes, which lays the ground for the development of novel pharmaceutical approaches.

List of scientific papers

I. Carina Fischer, Takahiro Seki, Sharon Lim, Masaki Nakamura, Patrik Andersson, Yunlong Yang, Jennifer Honek, Yangang Wang, Yanyan Gao, Fang Chen, Nilesh J. Samani, Jun Zhang, Masato Miyake, Seiichi Oyadomari, Akihiro Yasue, Xuri Li, Yun Zhang, Yizhi Liu and Yihai Cao. A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning. Nature Communications. 2017 Vol. 8: 2079.
https://doi.org/10.1038/s41467-017-02158-z

II. Takahiro Seki, Kayoko Hosaka, Carina Fischer, Sharon Lim, Patrik Andersson, Mitsuhiko Abe, Hideki Iwamoto, Yanyan Gao, Xinsheng Wang, Guo-Hue Fong and Yihai Cao. Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning. The Journal of Experimental Medicine. 2018 Vol. 215: 611.
https://doi.org/10.1084/jem.20171012

III. Takahiro Seki, Kayoko Hosaka, Sharon Lim, Carina Fischer, Jennifer Honek, Yunlong Yang, Patrik Andersson, Masaki Nakamura, Erik Näslund, Seppo Ylä-Herttuala, Meili Sun, Hideki Iwamoto, Xuri Li, Yizhi Liu, Nilesh J. Samani and Yihai Cao. Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat. Nature Communications. 2016 Vol. 7: 12152.
https://doi.org/10.1038/ncomms12152

IV. Jennifer Honek, Takahiro Seki, Hideki Iwamoto, Carina Fischer, Jingrong Li, Sharon Lim, Nilesh J. Samani, Jingwu Zang and Yihai Cao. Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues. Proceedings of the National Academy of Sciences of the United States of America. 2014 Vol. 111: 14906.
https://doi.org/10.1073/pnas.1415825111