Adipogenesis and insulin sensitivity in obesity are regulated by retinoid‐related orphan receptor gamma

Abstract

Obesity is a well-known risk factor for the development of secondary complications such as type 2 diabetes. However, only a part of the obese population develops secondary metabolic disorders. Here, we identify the transcription factor retinoid-related orphan receptor gamma (RORγ) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3. In vivo differentiation of adipocyte progenitor cells from Rorγ-deficient mice is enhanced and obese Rorγ−/− mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Rorγ−/− mice are protected from hyperglycemia and insulin resistance in the state of obesity. In adipose stromal-vascular fraction from obese human subjects, Rorγ expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity. Taken together, our findings identify RORγ as a factor, which controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. RORγ might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

Immunometabolism: Is it under the eye of the clock?

“…ROR␥ appears to play a role in metabolism through negative regulation of adipogenesis and insulin sensitivity. When overexpressed, ROR␥ leads to a decrease in the number of differentiated adipocytes in-vitro [131]. In Ror -/-mice, adipocyte generation is enhanced, but these cells are insulin sensitive, protecting the mice from obesity-induced hyperglycemia [131].…”

“…When overexpressed, ROR␥ leads to a decrease in the number of differentiated adipocytes in-vitro [131]. In Ror -/-mice, adipocyte generation is enhanced, but these cells are insulin sensitive, protecting the mice from obesity-induced hyperglycemia [131]. With ROR␣ and ROR␥ being crucial for lipid metabolism and gluconeogenesis, a role for these proteins in the development of diabetes and obesity-induced insulin resistance seems plausible.…”

Regulation of De Novo Adipocyte Differentiation Through Cross Talk Between Adipocytes and Preadipocytes

“…Conversely, hyperplasia is followed by a reduction in M1-type markers and an increase in anti-inflammatory "alternatively activated" M2 macrophages (11). Thus, hypertrophy is strongly associated with the development of insulin resistance and type 2 diabetes (4,5), whereas hyperplasia is associated with improved insulin sensitivity (6,12). Since changes in adipocyte size influence the adipokine profile, it can be envisaged that the balance of hypertrophy/hyperplasia leads to alterations in adipokine profiles, and this ultimately might affect disease progression.…”

Circadian rhythms and clocks in adipose tissues: current insights

“…Knockdown of the clock genes, either Bmal1 or Rev-Erbα, in cells inhibits adipocyte differentiation while mutations of two other clock components, Per2 or retinoid orphan receptor α (RORα), increase adipogenesis. [27][28][29][30][31][32] Both effects are mediated by peroxisome proliferator-activated receptor (PPARγ), a transcription factor crucial for terminal adipocyte differentiation, which is a direct adipose CCG. 33,34 Interestingly, Bmal1 seems to have a bimodal impact on adipocyte differentiation.…”