Obesity: the Many Faces of Leptin—A Novel Role for Leptin Signalling In

RESEARCH HIGHLIGHTS Nature Reviews Endocrinology 11, 129 (2015); published online 23 December 2014; doi:10.1038/nrendo.2014.231

OBESITY The many faces of leptin—a novel role for leptin signalling in obesity-induced hypertension

novel role for leptin in mediating The researchers compared C57BL/6J the increased blood pressure that is mice fed a chow diet with mice fed a high- A seen in individuals with obesity has fat diet (HFD). In the latter group, body been identified. The findings, published weight, leptin levels, heart rate and blood in Cell, stem from a collaboration between pressure progressively increased during the laboratories of Michael Cowley a 20-week recording period. All of these Zoonar/iStock/Thinkstock (Monash University, Clayton, Australia) effects were reversed when the mice in the and Sadaf Farooqi (University of HFD group lost weight after a 2-week chow Cambridge, UK); other researchers from diet. Mice deficient in leptin (ob/ob) or the USA and the UK were also involved. in the leptin receptor (db/db) had greater Obesity is a known risk factor for body weight than mice with diet-induced the development of hypertension, obesity (DIO), but did not have increased but the mechanistic link between the heart rate or increased blood pressure. two conditions is not well understood. Leptin treatment of ob/ob mice increased gene encoding the leptin receptor and “When I was an undergraduate student,” heart rate and blood pressure, effects that 48 control children of similar age and comments Cowley, “an argument was were attenuated over time as body weight body weight. Children without the leptin made that because the body of an decreased. These findings show that receptor had significantly lower systolic individual with obesity is much bigger obesity alone is not sufficient to cause the blood pressure than controls. These than the body of an individual without cardiovascular outcomes assessed in this observations underscore the role of leptin in obesity, the heart of those with obesity study and that leptin is required to mediate obesity‑induced hypertension in humans. had to work harder. However, some these effects. Cowley highlights three questions athletes such as rugby players have Inhibition of leptin function by use of his team plans to investigate. “Can we very large bodies yet do not have high an anti-leptin antibody or a leptin receptor determine which neurons in the DMH blood pressure.” antagonist led to significant reductions in transduce the effects of leptin, to where Leptin is produced in adipose tissue and heart rate and blood pressure in mice with they project, and what else they make? the levels of this hormone are therefore DIO, independent of body weight. Blocking What signalling system does leptin use in increased in individuals with obesity. The or inactivation of the leptin receptor in these particular neurons? Is it feasible to action of leptin in the hypothalamus to the DMH also led to similar body-weight- block this system and does this blocking regulate energy metabolism is well known. independent reductions in blood pressure in effectively reduce blood pressure?” “A long-standing body of work from mice with DIO. Further electrophysiological Farooqi and her team “are interested in Murray Esler, at the Baker IDI Heart and pharmacological experiments revealed using human genetics to identify and and Diabetes Institute in Melbourne, that DMH neurons that express the characterize the mechanisms involved Australia, had demonstrated correlations leptin receptor are necessary to trigger in severe obesity and its complications”. between leptin levels and blood pressure, the effects of leptin in the mediation of Cowley comments that, from now on, and between leptin levels and the activity obesity‑induced increases in blood pressure. clinicians will no longer say to their patients of the sympathetic nervous system,” Humans who are homozygous for a loss- that “obesity increases your risk of elevated explains Cowley. “We had also previously of-function mutation in the leptin gene blood pressure, so you should lose some shown that leptin acts on the dorsomedial develop early-onset obesity. The researchers weight”, but will be able to say that “your hypothalamus (DMH) to increase studied eight children with genetic leptin obesity causes the secretion of a hormone sympathetic nervous system tone to deficiency and 42 age-matched and BMI- that increases your blood pressure, so brown adipose tissue.” matched children without leptin deficiency. you must lose weight to reduce your These findings raise the possibility that Diastolic blood pressure was equivalent in blood pressure”. leptin also drives sympathetic tone to the the two groups, but children with leptin Joana Osório cardiorenal system. “We decided to do deficiency had significantly lower systolic this project to see if we could uncover this blood pressure than control children. link and establish a relationship between Another analysis involved 12 children Original article Simonds, S. E. et al. Leptin mediates the obesity and high blood pressure,” say with severe obesity who were homozygous increase in blood pressure associated with obesity. Cell Cowley and Farooqi. for a loss-of-function mutation in the 159, 1404–1416 (2014)