C/EBP  regulates body composition, energy balance-related hormones and tumor growth

Abstract

The prevalence of obesity, an established epidemiologic risk factor for many chronic diseases including cancer, has been steadily increasing in the US over several decades. The mechanisms used to regulate energy balance and adiposity and the relationship of these factors to cancer are not completely understood. Here we have used knockout mice to examine the roles of the transcription factors CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta in regulating body composition and systemic levels of hormones such as insulin-like growth factor-1 (IGF-1), leptin and insulin that mediate energy balance. Dual-energy X-ray absorptiometry showed that C/EBPbeta, either directly or indirectly, modulated body weight, fat content and bone density in both males and females, while the effect of C/EBPdelta was minor and only affected adiposity and body weight in female animals. Levels of IGF-1, leptin and insulin in the serum were decreased in both male and female C/EBPbeta(-/-) mice, and C/EBPbeta was associated with their promoters in vivo. Moreover, colon adenocarcinoma cells displayed reduced tumorigenic potential when transplanted into C/EBPbeta-deficient animals, especially males. Thus, C/EBPbeta contributes to endocrine expression of IGF-1, leptin and insulin, which modulate energy balance and can contribute to cancer progression by creating a favorable environment for tumor cell proliferation and survival.

CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption

“…Control C/EBP␤ KO mice had significantly lower BMC, BMD, BVF, and TbN than control wild-type mice, similar to recent findings (54,68). Diabetes caused trabecular bone loss in both wildtype and KO mice, as demonstrated by lower trabecular BMC, BMD, BVF, and TbTh (Fig.…”

“…C/EBP␤ Ϫ/Ϫ mice were smaller than wild-type mice: they have lower total body, muscle (tibialis anterior), and peripheral fat pad mass (femoral fat pad, located outside of the femur) ( Table 1), as seen in past studies (34,54). Consistent with a diabetic phenotype, both wild-type and KO diabetic mice lost weight.…”

“…Although many studies have demonstrated the importance of C/EBP␤ for adipocyte phenotype in vitro (9,12,64,66) and in vivo (40,50,54), effects of C/EBP␤ on bone marrow adiposity have not been extensively examined. Our findings demonstrate no significant difference between marrow adipocyte numbers in wild-type and C/EBP␤ Ϫ/Ϫ mice (Fig.…”

“…Overexpression of C/EBP␤ alone induces adipocyte differentiation in NIH-3T3 fibroblasts, while LIP overexpression can prevent it (64,66). Total deficiency of C/EBP␤ protects mice from obesity and reduces body fat mass (40,50,54). Combined knockout of C/EBP␤ and C/EBP␦ leads to an even greater block to the adipocyte phenotype and adiposity (58).…”

“…C/EBP␤ is normally expressed during early and late stages of osteoblast differentiation, with decreased expression during middle stages (17,23). Complete knockout of C/EBP␤ in mice results in decreased total body mass and total bone mineral density (BMD) (54). Similarly, targeted expression of the C/EBP␤ inactive form, LIP, to osteoblasts results in bone loss due to decreased bone formation (19).…”