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Nuclear Receptors (Co-Leaders: Peter Tontonoz and Ron Evans)

Our faculty are pioneers in the nuclear receptor field, particularly as it relates to the chemistry and biology of nuclear hormone receptors and the regulation of metabolism, inflammation, insulin sensitivity, exercise biology and lipid signaling. Highlights include the following.

  1. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis, by DRC members Tontonoz, Whittledge, and others in Nature (2016). Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Tontonoz and colleagues showed that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis, and identified the long non-coding RNA LeXis as a mediator of this effect. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.
  2. Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females, by DRC members Hevener, Tontonoz, Schenk, Lusis and others in Science Translational Medicine (2016). Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in muscle-specific ERα knockout (MERKO) mice. Hevener and colleagues demonstrate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.
  3. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance, by DRC members Evans, Olefsky, Brenner, Saltiel and others in Nature Medicine (2016). The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. Evans and colleagues show that the gut-restricted FXR agonist fexaramine reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue. These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
  4. PPARδ promotes running endurance by preserving glucose, by DRC member Evans, and others inCell Metabolism (2017). Management of energy stores is critical during endurance exercise; a shift in substrate utilization from glucose toward fat is a hallmark of trained muscle. Evans and colleagues showed that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies, and, unavoidably, the enhancement of athletic performance.omotes running end017). Management of energy stores is critical during endurance exercise; a shift in substra