RESUMEN
Background & Aims: Although fat loss is observed in patients with cholestasis, how chronically elevated bile acids (BAs) impact white and brown fat depots remains obscure. Methods: To determine the direct effect of pathological levels of BAs on lipid accumulation and mitochondrial function, primary white and brown adipocyte cultures along with fat depots from two separate mouse models of cholestatic liver diseases, namely (i) genetic deletion of farnesoid X receptor (Fxr); small heterodimer (Shp) double knockout (DKO) and (ii) injury by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), were used. Results: As expected, cholestatic mice accumulate high systemic BA levels and exhibit fat loss. Here, we demonstrate that chronic exposure to pathological BA levels results in mitochondrial dysfunction and defective thermogenesis. Consistently, both DKO and DDC-fed mice exhibit lower body temperature. Importantly, thermoneutral (30 °C) housing of the cholestatic DKO mice rescues the decrease in brown fat mass, and the expression of genes responsible for lipogenesis and regulation of mitochondrial function. To overcome systemic effects, primary adipocyte cultures were treated with pathological BA concentrations. Mitochondrial permeability and respiration analysis revealed that BA overload is sufficient to reduce mitochondrial function in primary adipocytes, which is not as a result of cytotoxicity. Instead, we found robust reductions in uncoupling protein 1 (Ucp1), PR domain containing 16 (Prdm16), and deiodinase, iodothyronine, type II (Dio2) transcripts in brown adipocytes upon treatment with chenodeoxycholic acid, whereas taurocholic acid led to the suppression of Dio2 transcript. This BA-mediated decrease in transcripts was alleviated by pharmacological activation of UCP1. Conclusions: High concentrations of BAs cause defective thermogenesis by reducing the expression of crucial regulators of mitochondrial function, including UCP1, which may explain the clinical features of hypothermia and fat loss observed in patients with cholestatic liver diseases. Impact and Implications: We uncover a detrimental effect of chronic bile acid overload on adipose mitochondrial function. Pathological concentration of different BAs reduces the expression of distinct genes involved in energy expenditure, which can be mitigated with pharmacological UCP1 activation.
RESUMEN
The intestinal epithelium is continuously regenerated through proliferation and differentiation of stem cells located in the intestinal crypts. Obesity affects this process and results in greater stem cell proliferation and altered tissue growth and function. Obesity-induced high levels of insulin and insulin-like growth factor-1 in the stem cell niche are found to impact proliferation in rodents indicating that insulin and insulin-like growth factor-1 receptors may play a role in modulating intestinal epithelial stem cell proliferation. To determine whether insulin or insulin-like growth factor-1 can induce proliferation in human intestinal epithelial stem cells, and if two downstream insulin and insulin-like growth factor-1 receptor signaling pathways, PI3K/Akt and ERK, are involved, we used primary small intestinal epithelial crypts isolated from obese humans and investigated (1) the effect of insulin or insulin-like growth factor-1 on crypt proliferation, and (2) the effect of insulin and insulin-like growth factor-1 signaling inhibitors on insulin or insulin-like growth factor-1-induced proliferation. We found that insulin and insulin-like growth factor-1 enhanced the proliferation of crypt cells, including intestinal epithelial stem cells. Inhibition of the PI3K/Akt pathway attenuated insulin and insulin-like growth factor-1-induced proliferation, but inhibition of the ERK pathway had no effect. These results suggest that the classical metabolic PI3K pathway and not the canonical proliferation ERK pathway is involved in the insulin/insulin-like growth factor-1-induced increase in crypt proliferation in obese humans, which may contribute to abnormal tissue renewal and function. Impact statement This study investigates if insulin or insulin-like growth factor-1 (IGF-1) induces intestinal epithelial proliferation in humans, and if insulin and IGF-1 receptor signaling is involved in this process in obesity. Although obesity-induced high levels of insulin and IGF-1 in the stem cell niche are found to impact the proliferation of intestinal epithelial stem cells in rodents, we are the first to investigate this effect in humans. We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts (including stem cells and other crypt cells) isolated from obese humans, and PI3K/Akt, and not ERK signaling was involved in insulin or IGF-1-induced proliferation. The imbalance in signaling between PI3K/Akt and ERK pathways may point to a pathway-specific impairment in insulin/IGF-1 receptor signaling. We propose that this may contribute to reciprocal relationships between insulin/IGF-1 receptor resistance and intestinal epithelial proliferation that leads to abnormal tissue renewal and function.