Brown adipose tissue development & involution
Obesity is a global epidemic. The excessive fat accumulation in white adipose tissue (WAT) and visceral organs is a major risk factor for many diseases, including type 2 diabetes, hypertension, heart disease, and some types of cancers.
In contrast to classic WAT, brown adipose tissue (BAT) and “brown-like” beige adipocytes in WAT burn fat and dissipate chemical energy as heat (thermogenesis). One of the fundamental goals in the field is to identify factors and approaches that recruit or activate thermogenic tissues. However, these efforts have been overshadowed by the fact that BAT in humans undergoes age-dependent involution or atrophy. Understanding the involution process of BAT can provide insights into preserving or regenerating the tissue to treat obesity and comorbidities. We use integrated approaches, including comparative physiology, next generation single cell RNA sequencing, and functional mouse genetics, to identify tissue-intrinsic and -extrinsic mechanisms that govern the age-associated BAT involution.
In humans, there are two spatiotemporally distinct phases of BAT ontogeny. BAT first appears mainly in interscapular and peri-renal regions during mid-gestation. While maximally recruited in infants, the interscapular BAT rapidly atrophies till barely detectable in adults. The second developmental phase occurs postnatally and gives rise to anatomically dispersed BAT in cervical, supraclavicular, and axillary areas in adult humans. The cervical-supraclavicular BAT peaks its prevalence in adolescence and then progressively involutes in an age-dependent manner. Compared to the interscapular BAT in early life, the developmental origins and functional differences of the metabolically active BAT around neck in adult humans remain enigmatic. We currently use mouse as the model to study the lineage development and metabolic impact of the neck BAT.
Adipose tissue associated with lymphoid organs
With obesity and aging, adipocytes also accumulate within the primary lymphoid organs including bone marrow and thymus. Excess fat deposition is associated with the functional decline of the skeletal and hematopoietic systems, causing bone loss, marrow adiposity, myeloproliferation, and immunosenescence.
We show that marrow adipose tissue is essential for the steady-state and skewed hematopoiesis upon metabolic stress, by providing the niche factor SCF. Protein O-GlcNAcylation, by reciprocally modulating RUNX2 and PPARγ, controls the differentiation of osteoblasts vs. adipocytes in the bone marrow. Several investigations are ongoing in the lab to determine the lineage identity, regulatory signals, and functional impact of lymphoid organ-associated adipose tissue during obesity and aging.
1. Huang Z, Zhang Z, Moazzami Z, Heck R, Hu P, Nanda H, Ren K, Sun Z, Bartolomucci A, Gao Y, Chung D, Zhu W, Shen S, Ruan HB (2022). Brown adipose tissue involution driven by progressive restriction in progenitor competence. Cell Reports. 39(2): 110575.DOI: 10.1016/j.celrep.2022.110575.
2. Zhang Z, Huang Z, Ong B, Sahu C, Zeng H, Ruan HB. (2019). Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis. Haematologica. 104(9):1731-1743.
3. Wang Q, Tang J, Jiang S, Huang Z, Song A, Hou S, Gao X, Ruan HB. (2018). Inhibition of PPARγ, adipogenesis and insulin sensitivity by MAGED1. Journal of Endocrinology. 239(2): 167-180.
4. Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, Zhang K, Yin R, Wu J, Horvath TL, Yang X. (2014). O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell. 159(2): 306-317.
5. Huang Z, Ruan HB, Xian L, Chen W, Jiang S, Song A, Wang Q, Shi P, Gu X, Gao X. (2014) The stem cell factor/Kit signaling pathway regulates mitochondrial function and energy expenditure. Nature Communications. 5:4282.