Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity

Abstract

Retinoic acid-related orphan receptors RORα and RORγ play a regulatory role in lipid/glucose homeostasis and various immune functions, and have been implicated in metabolic syndrome and several inflammatory diseases. RORα-deficient mice are protected against age- and diet-induced obesity, hepatosteatosis, and insulin resistance. The resistance to hepatosteatosis in RORα-deficient mice is related to the reduced expression of several genes regulating lipid synthesis, transport, and storage. Adipose tissue-associated inflammation, which plays a critical role in the development of insulin resistance, is considerably diminished in RORα-deficient mice as indicated by the reduced infiltration of M1 macrophages and decreased expression of many proinflammatory genes. Deficiency in RORγ also protects against diet-induced insulin resistance by a mechanism that appears different from that in RORα deficiency. Recent studies indicated that RORs provide an important link between the circadian clock machinery and its regulation of metabolic genes and metabolic syndrome. As ligand-dependent transcription factors, RORs may provide novel therapeutic targets in the management of obesity and associated metabolic diseases, including hepatosteatosis, adipose tissue-associated inflammation, and insulin resistance.

Keywords: adipose tissue; circadian rhythm; diabetes; hepatosteatosis; inflammation; insulin-resistance; obesity; retinoic acid-related orphan receptor.

FIGURE 1

RORα functions as a positive regulator of hepatosteatosis, WAT-associated inflammation, and insulin-resistance in diet- and age-induced obesity. Loss of RORα inhibits the hepatic expression of lipogenic genes and suppresses the expression of proinflammatory genes and the infiltration of macrophages in WAT, and as a result protects against these pathologies.

FIGURE 2

In peripheral tissues, RORs function as intermediate regulators providing a link between clock proteins and their regulation of lipid and glucose metabolism. The oscillatory pattern of expression of RORγ is regulated by circadian clock proteins Bmal1 and Clock or Npas2 through E-box, whereas RORα does not exhibit a strong oscillatory pattern of expression. In turn, RORγ activates expression of several clock genes through ROREs together with RORα. Both RORα and RORγ regulate the circadian pattern of expression of target genes involved in lipid/glucose metabolism. ROR (ant)agonists may modulate the amplitude of peripheral clock oscillation of these metabolic outputs and might be useful in the treatment of insulin resistance, obesity, and tissue inflammation.