Nuclear receptors

The discovery of nuclear receptors provides a molecular approach to the study of regulation by fat-soluble hormones, vitamins and dietary lipids, as well as drug targets for associated diseases. Our long term goal is to understand how the nuclear receptor family of transcription factors regulates development, metabolism and cancer, using the skeleton and the mammary gland as model systems. A wide spectrum of cutting-edge tools will be employed, including mouse genetic and disease models, molecular and cellular biology, biochemistry, genomics, metabolomics, proteomics, stem cells and small molecules.

Currently, we focus on the receptor PPARγ (Peroxisome proliferator-activated receptor γ), which controls both metabolism and inflammation in normal physiology and diseases such as obesity, diabetes and atherosclerosis. The importance of PPARγ is accentuated by the widespread use of its ligands (TZDs) as drugs for the treatment of type II diabetes and insulin resistance.

Osteoclast and bone remodeling

Bone is a dynamic tissue that undergoes constant remodeling, balancing bone formation by osteoblasts and bone resorption by osteoclasts. When resorption outpaces formation, osteoporosis will occur. With the aging of the society, over 10 million Americans suffer from osteoporosis, leading to 1.5 million fractures and 40,000 deaths annually, while many others ending up in nursing homes. PPARγ inhibits osteoblast differentiation from mesenchymal stem cells by favoring adipocyte differentiation. Our recent study discovered that PPARγ also has a novel role of promoting osteoclast differentiation from hematopoietic stem cells. Importantly, these findings unravel a central role for PPARγ in the emerging connection between mineral and energy metabolism, linking skeletal disorders with metabolic syndrome. Furthermore, breast and prostate cancer has a strong propensity (>80%) to metastasize to the bone, causing osteolysis, hypercalcemia and intense pain. Our future research will:

  • Dissect the molecular mechanisms for osteoclast differentiation.
  • Determine the inter-cellular communication between osteoclast and osteoblast.
  • Study fracture healing, the bone regeneration in response to injury.
  • Understand the influence of obesity, diabetes and aging on bone remodeling.
  • Investigate osteoclast regulation of cancer bone metastasis.

Figure 1. Osteoclast differentiation.

Lactation in neonate health and breast cancer

Lactation is a metabolically demanding process yet crucial for the development of newborn mammals. Our recent study reveals that a targeted deletion of PPARγ in mice results in production of “toxic milk” containing elevated levels of inflammatory lipids. Surprisingly, ingestion of this “toxic milk” causes inflammation, alopecia and growth retardation in the nursing neonates. Genomic profiling reveals increased expression of lipid oxidation enzymes in the PPARγ deficient lactating mammary gland. Consistently, metabolomic profiling detects increased levels of oxidized free-fatty-acids in the pups nursed by PPARγ deficient mothers. Therefore, maternal PPARγ is pivotal for maintaining milk quality and protecting the nursing newborns. Moreover, this suggests a potential role for PPARγ in preventing the “developmental programming” of metabolic diseases. Also known as the “Barker Hypothesis”, this emerging theory predicts that the health of a woman during pregnancy and lactation could affect whether her child develops chronic diseases as an adult. Furthermore, epidemiological studies suggest that inflammation promotes cancer progression and metastasis. Our future research will:

  • Identify maternal genetic and dietary factors that ensure milk homeostasis and prevent neonatal inflammation.
  • Investigate the genetic circuitry in the neonates that ensure postnatal metabolic adaptation.
  • Explore the long term health consequences of“toxic milk”.
  • Unveil novel mechanisms and new therapeutic strategies for infantile disorders and inflammatory diseases.

Fig 2A. Maternal PPARγ deficiency causes aberrant lactation.

Figure 2B. Maternal PPARγ deficiency also causes skin inflammation in the nursing neonates.

 

Our research is funded by: