Reciprocal Regulation of Hepatic TGF-ß1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.

Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-ß1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-ß1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-ß1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-ß1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-ß1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-ß1→Foxo1→TGF-ß1 looping by deleting TGF-ß1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-ß1→Foxo1→TGF-ß1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. ARTICLE HIGHLIGHTS: Hepatic TGF-ß1 levels are increased in obese humans and mice. Hepatic TGF-ß1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-ß1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-ß1→Foxo1→TGF-ß1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.

Female Off-Farm Employment and Fertility Timing in Rural China.

Background: Advanced maternal age is associated with fetal outcomes such as higher risks of birth defects and very low birth weight. Off-farm employment is an important factor in fertility transition in many developing countries. This study investigated the association between off-farm employment and fertility timing among Chinese rural women. Method: Using data from the China Labor-force Dynamics Survey (CLDS), we employed the ordinary least squares and instrumental variable approaches to estimate the effect of female off-farm employment on fertility timing decisions as well as the differences in the effect across groups. Results: The results show that off-farm employment participation is significantly associated with a later age at first birth, and the effect is stronger for women participating in wage employment than in off-farm self-employment. The delayed effects on fertility timing are also more pronounced for less-educated women and low-income families, implying a heterogeneous effect in terms of women's socioeconomic status. Conclusion: Studies of the relationship between women's off-farm employment and fertility timing in rural areas of developing countries remain limited. This study provides important insights on this topic, and it lends support to efforts to design effective policies and practices to facilitate female employment, childbearing, and health promotion.