Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

Abstract

<jats:title>Abstract</jats:title><jats:p>Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. Using adipose selective deletion of β1 integrin (Itgb1<jats:sup>adipo-cre</jats:sup>) and Kindlin-2 (Kind2<jats:sup>adipo-cre</jats:sup>), we demonstrate here that active β1 and β3 integrins directly interact with the insulin receptor to regulate white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in lipodystrophy and systemic insulin resistance. Conversely, we find that brown adipose tissue of Kind2<jats:sup>adipo-cre</jats:sup> and Itgb1<jats:sup>adipo-cre</jats:sup> mice is chronically hyperactivated, and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole body metabolism.</jats:p>

Transforming growth factor β1 signaling links extracellular matrix remodeling to intracellular lipogenesis upon physiological feeding events

“…In accordance with the results, previous studies have shown that defects in lipogenesis-related factors, including ACC, SCD, ACLY, DGAT1/2 and BSCL2, lead to loss of adipose tissue and are associated with systemic metabolic abnormalities (44)(45)(46)(47)(48)(49)(50)(51). Similar phenotypes were found with defects of the extracellular matrix and related signaling molecules, including collagen, FBN, integrin, and FAK (52)(53)(54)(55)(56)(57).…”

Adipose Extracellular Matrix Remodeling in Obesity and Insulin Resistance

“…Thus, taken together, it is evident that it is the insulin resistnce in adipose tissue that leads to inflammation and not inflammation itself that leads to adipose tissue insulin resistance. In line with these findings, Ruiz-Ojeda et al [59] demonstrated that isolated adipocytes from subcutaneous WAT of adipose-specific knockout of Kindlin-2, an integrin activator, showed local insulin resistance read by reduced Akt phosphorylation and decreased glucose uptake. However, no differences were observed in the proinflammatory markers in the adipose tissue of chow diet-fed mice [59].…”

“…In line with these findings, Ruiz-Ojeda et al [59] demonstrated that isolated adipocytes from subcutaneous WAT of adipose-specific knockout of Kindlin-2, an integrin activator, showed local insulin resistance read by reduced Akt phosphorylation and decreased glucose uptake. However, no differences were observed in the proinflammatory markers in the adipose tissue of chow diet-fed mice [59].…”

“…11.2). Moreover, this study reveals how integrins contribute to brown fat thermogenesis mediated by the basal lamina of brown adipocytes, establishing integrin-extracellular matrix interactions as key regulators of adipose tissue function and whole body metabolism [59].…”

“…Indeed, adipose-specific loss of kindlin-2, a focal adhesion protein activating integrins, provokes lipodystrophy and metabolic disturbance in mice [19]. Likewise, Ruiz-Ojeda et al [59] have revealed that active integrins interact with the insulin receptor in adipocytes modulating WAT insulin sensitivity (Fig. 11.2).…”