Our long-range goal is to understand molecular pathways that govern brown fat development and function. In contrast to white fat, brown fat is a tissue that is specialized in energy expenditure. It is present in adult humans and its activity is inversely associated with human obesity. Thus, brown fat is potentially an attractive therapeutic target tissue for obesity and metabolic diseases. We are interested in how brown fat development and function is regulated by miRNAs, a class of small RNAs that do not encode protein yet control many developmental and cellular processes. We have identified a set of miRNAs that are selectively expressed in the brown fat. We found that, one of them, when expressed in the brown fat, remarkably expands the brown fat depots of mice, and as a result, the animals have less white fat mass and are resistant to diet-induced obesity. Our hypothesis is that this miRNA promotes brown fat cell differentiation by activating a cGMP- dependent signaling pathway. In the first aim, we will analyze in detail whether the expanded brown fat depots are true brown fat and are functional. We will determine whether the expanded brown fat improves metabolic parameters and enhances insulin sensitivity. We will determine whether the expanded brown fat prevents genetically predisposed obesity. In the second aim, we will perform cell culture studies to further validate that this miRNA promotes brown cell differentiation. We will examine whether the miRNA represses the expression of a negative regulator in the cGMP-dependent signaling pathway. In the third aim, we will determine whether the miRNA activates the cGMP-dependent signaling pathway. Our studies will likely provide useful information on whether mimics of this miRNA have therapeutic potentials for obesity and metabolic diseases.

Public Health Relevance

Alterations in pathways that regulate energy balance are responsible for obesity and metabolic diseases. Brown fat is a tissue that is specialized for energy expenditure. Brown fat is present in humans and is inversely correlated with obesity. Our studies address the underlying mechanisms controlling brown fat development and function, which will clearly be very useful for the development of new therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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University of Massachusetts Medical School Worcester
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United States
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Chen, Qingbo; Huang, Lei; Pan, Dongning et al. (2018) Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis. Cell Rep 22:2860-2872
Huang, Lei; Pan, Dongning; Chen, Qingbo et al. (2017) Transcription factor Hlx controls a systematic switch from white to brown fat through Prdm16-mediated co-activation. Nat Commun 8:68
Pan, Dongning; Huang, Lei; Zhu, Lihua J et al. (2015) Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity. Dev Cell 35:568-583
Pan, Dongning; Mao, Chunxiao; Quattrochi, Brian et al. (2014) MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat Commun 5:4725