The LXCXE Retinoblastoma Protein-Binding Motif of FOG-2 Regulates Adipogenesis

Abstract

GATA transcription factors and their FOG cofactors play a key role in tissue-specific development and differentiation, from worms to humans. Mammals have six GATA and two FOG factors. We recently demonstrated that interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation. We show here that the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Unlike GATA-1, which inhibits cell division, FOG-2 promotes proliferation. Mice with a knockin of a Fog2 gene bearing a mutated LXCXE pRb-binding site are resistant to obesity and display higher rates of white-to-brown fat conversion. Thus, each component of the GATA/FOG complex (GATA-1 and FOG-2) is involved in pRb/E2F regulation, but these molecules have markedly different roles in the control of tissue homeostasis.

The integrity of the FOG‐2 LXCXE pRb‐binding motif is required for small intestine homeostasis

“…We therefore analysed biochemical and metabolic parameters in the plasma of Fog2 Rb− / Rb− mice fed a regular diet (Table ). These mice had abnormally low levels of C‐peptide, a feature that has been reported to be associated with lower levels of insulin and higher levels of glucagon (Goupille et al., ). We detected no significant differences in resistin and albumin levels between Fog2 WT/WT mice and Fog2 Rb−/Rb− mice, confirming our previous observations that mutant mice are not insulin‐resistant.…”

“…Fog2 Rb− / Rb− mice display significantly smaller increases in body weight (BW) and have a significantly shorter body length (BL) than wild‐type mice during adulthood, on both low‐ and high‐fat diets (Goupille et al., ). We therefore studied the growth curve of Fog2 Rb− / Rb− mice fed a regular diet, from the neonatal period until late adulthood.…”

“…We previously showed that FOG‐2 is expressed in adipose tissue and that mutation of the pRb‐binding LXCXE motif results in markedly smaller numbers of adipocytes and the browning of white adipose tissue. These effects result in resistance to cold stress and obesity in Fog2 Rb− / Rb− mice, due to both cell‐intrinsic (preadipocyte) and ‐extrinsic processes potentially involving other metabolic organs, such as the central nervous system, liver and intestine (Goupille et al., ). We show here that (1) FOG‐2 is expressed in the small intestine, (2) the pRb‐binding LXCXE motif controls the homeostasis and physiological adaptation of the small‐intestine crypt–villus axis, (3) FOG‐2–pRb interaction has an intrinsic function in incretin hormone (GIP) expression, (4) hepatic IGF‐I plays an extrinsic role in small‐intestine physiology, in global homeostasis in Fog2 Rb− / Rb− mice, (5) FOG‐2 Rb− mutation highlights the interplay between GATA–FOG and the cell‐cycle regulator pRb–E2F in the control of intestinal cell fate and body weight homeostasis.…”

“…FOG‐2 and GATA functions are closely linked. We have shown that variations of GATA–FOG complexes influence either GATA1–Rb (Kadri et al., ) or FOG‐2–Rb complexes (Goupille et al., ). We hypothesized that the binding of FOG‐2 to pRb regulates E2F–pRb complexes and many physiological and pathological processes.…”

“…Rb1 has been reported to be involved in intestinal development and differentiation (Guo, Longshore, Nair, & Warner, ; Yang & Hinds, ), and Rb1 −/− mice have been found to have lower levels of ossification than wild‐type mice (Berman et al., ). We recently reported an intrinsic role for FOG‐2–pRb interaction in adipose tissue and in the liver (Goupille et al., ). The pathophysiological impact of FOG‐2 on the functions of GATA and pRb in small intestine homeostasis remains unknown, and this study aimed to investigate this impact.…”