Twenty-six compelling conversations

Since May 2012, the JCI has aired twenty-six interviews with twenty-eight notable scientists for the series Conversations with Giants in Medicine. In the highlight reel to accompany the October 2014 issue, we’ve chosen some of the most memorable vignettes from the Conversations — stories that give life to the life sciences.

Targeting estrogen receptors to prevent binge eating

Binge eating is associated with obesity and depression. This disorder is more prevalent in women, and there is an apparent correlation between low estrogen levels and this behavior. In this episode, Yong Xu, Xuehong Cao, and Pingwen Xu demonstrate that estrogen replacement therapy attenuates binge eating behaviors in ovariectomized mice and that this effect was mediated by the estrogen receptor-α (ERα) in serotonergic neurons of the dorsal raphe nuclei (DRN). Moreover, systemic delivery of a glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate, which targets estrogen to GLP-1-expressing regions like the DRN, reduced binge eating in ovariectomized females. The results of this study suggest that ERα in the DRN has potential as therapeutic target for treating binge eating–associated disorders.

Examining the role of cullin 3 in hyperkalemic hypertension

Familial hyperkalemic hypertension (FHHt) is a rare monogenic disease that results from mutations in the kinases WNK1 and WNK4 or mutations in the ubiquitin ligase cullin 3 (CUL3) or the CUL3 substrate adaptor kelch-like 3 (KLHL3). Disease-associated mutations increase WNK kinase activity and thereby enhance activity of the Na-Cl transporter (NCC), which increases blood pressure and potassium levels. In this episode, David Ellison and colleagues reveal that FHHt-associated CUL3 mutant CUL3Δ403-459 exhibits enhanced ubiquitin ligase activity, leading to KLHL3 degradation and a subsequent increase in WNK kinase abundance. Moreover, kidney-specific deletion of Cul3 resulted in renal dysfunction, inflammation, and fibrosis in mice. This study provides insight in to the pathological mechanisms underlying FHHt-causing CUL3 mutations and demonstrates an essential role for CUL3 in the kidney.

Identification of weight loss-mediating liraglutide targets

The type 2 diabetes drug liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist that lowers blood glucose and reduces body weight. Liraglutide is being investigated for clinical use as a treatment for obesity; however, the mechanism of action underlying the associated weight loss is not clear. In this episode, Lotte Bjerre Knudsen and colleagues reveal that liraglutide mediates weight loss via neurons in the arcuate nucleus. GLP-1R signaling activated centrally projecting neurons that express proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART neurons), which regulate appetite and are activated by leptin and insulin. Liraglutide also inhibited neuropeptide Y-expressing neurons, which enhance appetite. The results of this study provide important insight into how liraglutide mediates weight loss.

Lasker Giants

For the last five years, the JCI has had the privilege of working with the Albert and Mary Lasker Foundation to write profiles on the prizewinners. Coverage of the 2014 laureates will be featured in the October issue. In addition to the news features on the prizes, we have had the pleasure of interviewing several of the previous years’ laureates for the series “Conversations with Giants in Medicine.”