Type 2 diabetes mellitus is a complex
metabolic disease that occurs when insulin secretion can no longer compensate
insulin resistance in peripheral tissues. At the molecular level,
insulin resistance correlates with impaired
insulin signalling. This review provides new insights into the molecular mechanisms of
insulin action and resistance in brown adipose tissue and pinpoints the role of this tissue in the control of
glucose homeostasis. Brown adipocytes are target cells for
insulin and
IGF-I action, especially during late foetal development when
insulin supports survival and promotes both adipogenic and thermogenic differentiation. The main pathway involved in
insulin induction of adipogenic differentiation, monitored by
fatty acid synthase expression, is the cascade
insulin receptor substrate (IRS)-1/
phosphatidylinositol 3-kinase (PI3K)/Akt.
Glucose transport in these cells is maintained mainly by the activity of GLUT4. Acute
insulin treatment stimulates
glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS-2/PI3K, and the downstream targets Akt and
protein kinase C zeta. Tumour
necrosis factor (
TNF-alpha) caused
insulin resistance on
glucose uptake by impairing
insulin signalling at the level of IRS-2. Activation of stress
kinases and
phosphatases by this
cytokine contribute to
insulin resistance. Furthermore, brown adipocytes are also target cells for
rosiglitazone action since they show a high expression of
peroxisome proliferator activated receptor gamma, and
rosiglitazone increased the expression of the thermogenic
uncoupling protein 1.
Rosiglitazone ameliorates
insulin resistance provoked by
TNF-alpha, completely restoring
insulin-stimulated
glucose uptake in parallel to the
insulin signalling cascade. Accordingly, foetal brown adipocytes represent a model for investigating
insulin action, as well as for the mechanism by which
rosiglitazone increase
insulin sensitivity under situations that mimic
insulin resistance.