Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues

Abstract

The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1 adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function. These biomechanical signaling mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue

“…In brown adipocytes, a reorganization of cytoskeletal proteins occurs upon adrenergic stimulation, which strongly mimics that of cardiomyocytes. Specifically, a PKA-dependent activation of L-type Ca 2+ channels is elicited that facilitates an influx of Ca 2+ , promoting the ATPase activity of the actomyosin complex (Tharp et al, 2018). Interestingly, as reported in the protein interaction network depicted in Fig.…”

“…More recently, Tharp et al (Tharp et al, 2018) demonstrated that favoring Ca 2+ -dependent actomyosin mechanics promotes thermogenic capacity of brown adipocytes. Specifically, under this circumstance, the mechanosensitive activation of YAP/TAZ transcription factors is elicited, thereby driving the expression of Ucp1 and other thermogenic genes (Tharp et al, 2018). Notably, we found a significant up-regulation of genes that form the actomyosin complex, arguing that the muscle signatures promoted by LPHC diet and AAR could participate in the thermogenic signaling cascade.…”

“…Recently, the rearrangement of the adipocyte cytoskeleton towards muscle-like signatures has been demonstrated to be fundamental for sustaining non-shivering thermogenesis. In particular, tensional responses generated by actomyosin are critical for the acute induction of oxidative metabolism and uncoupled respiration (Tharp et al, 2018). Moreover, it has been revealed that a set of beige adipocyte precursors may also differentiate in response to thermal stress through a glycolytic myogenic intermediate that is required for cellular homeostasis and survival (Chen et al, 2019).…”

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

“…β AR signaling is established to increase the contractility of cardiac myocytes (71) and to decrease the traction stresses of human airway smooth muscle cells (72). Recent findings show that activating β AR in adipose cells results in increased NMII activity and cell contractility, albeit through a Ca 2+ -MLCK pathway (73). Taken together, our observations contribute to the growing literature that shows β AR activation regulates force generation across a range of cell types through slightly different mechanisms; such findings suggest that β AR regulation of cellular mechanotype is a convergent phenomenon that is essential to cellular homeostasis.…”

How the mechanobiome drives cell behavior, viewed through the lens of control theory

“…The increase in elastic modulus is driven by AMPK activation, highlighting the role of AMPK as a transducer of metabolic signals to cellular mechanics (Hamann et al, 2017). More recently, another study has demonstrated a myosin II-dependent increase in stiffness of brown/beige adipose tissue and isolated brown adipocytes in response to cold challenge (Tharp et al, 2018). Here, actomyosin contractility was critical for the thermogenic capacity of the cells and the induction of uncoupled respiration through YAP/TAZ-mediated gene regulation (Tharp et al, 2018).…”