Osteopontin Is Required for the Early Onset of High Fat Diet-Induced Insulin Resistance in Mice

Abstract

BackgroundInsulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined.Methodology and Principal FindingsWe initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species. OPN regulates inflammation and is implicated in pathogenic maladies resulting from chronic obesity. Thus, we tested the hypothesis that OPN is involved in the early development of insulin resistance using a 2–4 week high fat diet (HFD) model. OPN KO mice fed HFD for 2 weeks were completely protected from the severe skeletal muscle, liver and adipose tissue insulin resistance that developed in wild type (WT) controls, as determined by hyperinsulinemic euglycemic clamp and acute insulin-stimulation studies. Although two-week HFD did not alter body weight or plasma free fatty acids and cytokines in either strain, HFD-induced hyperleptinemia, increased adipose tissue inflammation (macrophages and cytokines), and adipocyte hypertrophy were significant in WT mice and blunted or absent in OPN KO mice. Adipose tissue OPN protein isoform expression was significantly altered in 2- and 4-week HFD-fed WT mice but total OPN protein was unchanged. OPN KO bone marrow stromal cells were more osteogenic and less adipogenic than WT cells in vitro. Interestingly, the two differentiation pathways were inversely affected by HFD in WT cells in vitro.ConclusionsThe OPN KO phenotypes we report reflect protection from insulin resistance that is associated with changes in adipocyte biology and adipose tissue inflammatory status. OPN is a key component in the development of HFD-induced insulin resistance.

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

“…Currently, OPN has been implicated in the pathogenesis of insulin resistance, obesity, and diabetes [5] . The pharmacological and genetic inhibition of OPN has mitigated hepatic and adipose tissue inflammation, improved obesityinduced insulin resistance in hepatic and adipose tissue, attenuated hepatic steatosis, and prevented the upregulation of gluconeogenic genes in the liver [6][7][8][9] , suggesting that OPN is an important player in the development of insulin resistance and diabetes.…”

“…A high level of OPN is associated with fat storage in adipose tissue, accumulation of adipose tissue macrophages, adipose tissue inflammation, and adipocyte hypertrophy [6][7][8][9] . In addition, adipocytes can synthesize OPN.…”

“…In addition, adipocytes can synthesize OPN. In the early stage of high fat diet (HFD) consumption, adipose tissue showed altered OPN isoform expression, but total OPN protein was unchanged [8] . In agreement with this finding, high levels of OPN mRNA were found in the adipose tissues of obese and insulin-resistant humans and rats [8] .…”

“…In the early stage of high fat diet (HFD) consumption, adipose tissue showed altered OPN isoform expression, but total OPN protein was unchanged [8] . In agreement with this finding, high levels of OPN mRNA were found in the adipose tissues of obese and insulin-resistant humans and rats [8] . Mice exposed to chronic HFD exhibited dramatically increased plasma OPN levels and OPN protein abundance in adipose tissue [7,8] .…”

Peripheral signalling involved in energy homeostasis control

“…Expression of osteopontin is dramatically increased in adipose tissue from obese individuals (449,454,455) , suggesting the important role that this protein has in the molecular alterations that take place during adipose tissue enlargement. Moreover, osteopontin has been suggested to play a pivotal role linking obesity to insulin resistance development by promoting inflammation and the accumulation of macrophages in adipose tissue (450,453,456) . Higher levels of expression of osteopontin have been shown to be related to macrophage accumulation in adipose tissue and to liver steatosis in morbidly obese subjects (457) , which promote fibrosis progression in non-alcoholic steatohepatitis (458) .…”