Myosin 1c taking adrenergic metabolism for a spin: more than a motor protein

Abstract

Metabolic diseases like type II diabetes (T2D) and obesity largely stems from an unbalanced energy homeostasis with the fails of the insulin pathway to the point in which the glucose homeostasis is severely disturbed leading to hyperglycemia. We have investigated if the β-adrenergic signaling pathways, in both brown adipose tissue (BAT) and skeletal muscle, could be used as a strategy to alleviate metabolic disease.

As an important protein regulating energy metabolism, Akt has been an interesting target for study also in BAT, but its role in glucose uptake downstream the β-adrenergic receptors (β-ARs) have had conflicting outcomes. We have therefore made efforts to separate Akt and insulin from the β-adrenergic pathway and shown that Akt is not involved in β-adrenergic glucose uptake or thermogenesis in the brown adipocyte and norepinephrine (NE)-driven glucose clearance in vivo (Paper I). We have also shown that a β2-adrenergic agonist, clenbuterol, at low dose, can be used to induce glucose uptake to skeletal muscle, glucose clearance and increase insulin sensitivity in diet-induced obese mice, independently of insulin (Paper II). Administrating an agonist that binds to either the β-ARs on BAT or on skeletal muscle, at low dose to minimize cardiovascular adverse effects, would initiate processes independent of Akt and insulin, and could therefore be administered to patients with T2D to target idle assets.

Further, we have identified Myosin 1c (Myo1c) as a major regulator of basal protein kinase A (PKA) activity and basal glucose uptakein the brown adipocyte (Paper III) and also as a cofactor in chromatin remodeling for uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1α) transcription in the thermogenic adipocyte (Paper IV). These novel functions of Myo1c will open up the possibilities for future explorations concerning motor proteins in thermogenic adipocytes.

This thesis has expanded current understanding about the independence of Akt and insulin in β-adrenergic metabolism as well as identifying Myo1c as a key component of the β-adrenergic pathway in the thermogenic adipocyte. The work presented herein will hopefully contribute to further exploration into adrenergic signaling in BAT and skeletal muscle.

Keywords: Glucose uptake, Glucose transporter, Brown adipose tissue, White adipose tissue, Skeletal muscle, Myosin1c, Nuclear myosin I, Physiology.

Join via Zoom