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Actomyosin mediated tension orchestrates thermogenic programs in adipocytes

  • Author(s): Tharp, Kevin Menard
  • Advisor(s): Stahl, Andreas
  • et al.
Abstract

Innovative approaches to shift energy balance are urgently needed to combat metabolic disorders such as obesity and diabetes. One promising approach has been the expansion or activation of thermogenic adipose tissues to improve metabolic homeostasis. My doctoral studies presented in the following text have identified novel approaches to translate adipose based metabolic therapeutics and the underlying mechanisms by which thermogenic adipocytes establish their therapeutically applicable metabolic capacity.

In chapter I, I present a novel biomaterial technology optimized to expand metabolically beneficial thermogenic adipose depots in vivo. This system enabled me to determine the degree of metabolic enhancement possible with the exogenous expansion of thermogenic adipose depots. To generate therapeutic adipose implants I modified hyaluronic acid-based hydrogels to support the differentiation of white fat derived multipotent stem cells (ADMSCs) into lipid accumulating, uncoupling protein 1 (UCP1) expressing thermogenic adipocytes. Subcutaneous implantation of the synthetic tissues successfully attracted host vasculature and persisted for several weeks and the implant recipients demonstrated elevated core body temperature during cold challenges, enhanced respiration rates, improved glucose homeostasis, and reduced weight gain demonstrating the therapeutic merit of this highly translatable approach.

In chapter II, I outline the experimentation leading to the discoveries presented in chapter III as well as thoroughly review pertinent tissue engineering strategies. Specifically, I sought to define the mechanism by which synthetic ECM components identified in chapter I could alter differentiation outcomes of preadipocytes to yield greater thermogenic capacity.

In chapter III, I demonstrate that actomyosin-based mechanical responses provide a critical differentiation cue for the development of thermogenic adipocytes. Since I had determined that the hydrogel optimization techniques described in chapter I were likely acting through cytoskeletal-mediated processes I examined the role of cytoskeletal structure and tension in thermogenic adipose development. I identified that the muscle-like gene expression patterns of UCP1+ adipocytes are critical for the acute induction of oxidative metabolism and uncoupled respiration and regulate mechanosensitive transcriptional co-activators, YAP/TAZ, that control thermogenic gene expression.

This dissertation establishes the role of physical mechanics in the development and function of thermogenic adipocytes which may engender future metabolic therapeutics.

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