The AdipoChaser mouse: A model tracking adipogenesis in vivo

Abstract

White adipose tissue is considered to have high plasticity. Dynamic, abnormal expansion of white adipose tissue leads to obesity and associated metabolic disorders. Due to technical limitations, the life cycle and turnover rates of different white adipose depots during development and under various physiological conditions and environmental challenges has been assessed only through highly indirect approaches. We have recently described a system for the inducible, permanent labeling of mature adipocytes, the "AdipoChaser" mouse. Utilizing this AdipoChaser mouse model, we found that epididymal fat depots initiate adipogenesis after prolonged high fat diet feeding, whereas subcutaneous fat depots merely undergo hypertrophy and have a very low rate of adipogenesis. During cold exposure or β-3 agonist-induced "browning" of subcutaneous fat depot, most of the beige adipocytes arise from de novo adipogenesis. We also found that cold exposure or β-3 agonist stimulation induces massive white adipogenesis in the epididymal fat depot. Developmentally, adipocytes in the gonadal fat depot are differentiated postnatally, between birth and sexual maturation, while adipocytes in the subcutaneous fat are differentiated between embryonic days 14-18. Our study shed new insights into the developmental aspects of adipose tissue and its dynamics under a number of different physiological challenges.

Keywords: AdipoChaser; adipogenesis; beige adipocyte; obesity.

Figure 1. Schematic model showing the AdipoChaser mouse model and adipogenesis found in different fat depots. (A) The AdipoChaser mouse model: Prior to doxycycline treatment, every white adipocyte is LacZ-negative (adipocytes surrounded by red circles). After doxycycline exposure, all white adipocytes are LacZ-positive (adipocytes surrounded by blue circles). After doxycycline withdrawal, if mice are kept under conditions that induce adipogenesis, new adipocytes will be observed as LacZ-negative adipocytes (adipocytes surrounded by red circles with red glow). (B) Adipogenesis in eWAT in adult mouse: Prolonged HFD feeding (more than 1 mo), cold exposure, and β-3 treatment induce adipogenesis (white adipocyte) in eWAT. (C) Adipogenesis in sWAT in the adult mouse: HFD feeding only induces hypertrophy in sWAT; cold exposure and β-3 treatment-induced beige adipocytes within sWAT are from de novo adipogenesis. (D) The development of eWAT: Adipocytes in the eWAT are differentiated postnatally between birth and sexual maturation. LacZ expression in adipocytes is pulsed at postnatal day (P) 10 (doxycycline withdrawal), new white adipocytes are observed at P28 and there are more white adipocytes by P56. (E) The development of sWAT: All the adipocytes in the sWAT start to differentiate between embryonic day (E) 14 and E18, but the differentiation takes much longer and finishes postnatally. LacZ expression in adipocytes is pulsed at E18 (doxycycline withdrawal), no new white adipocytes are observed at P28 or P56.

Figure 2. Newly differentiated adipocytes are not necessarily small in size. (A and B) Representative β-gal staining of sWAT from 28 d old female and male mice. The mothers of these mice were on doxycycline diet during embryonic day 9 to embryonic day 16. Pink arrows, LacZ-negative adipocytes that have relative large cell sizes; blue arrows, LacZ-positive adipocytes that have relative small cell sizes.