RESEARCH HIGHLIGHTS Nature Reviews Neuroscience | AOP, published online 24 December 2014; doi:10.1038/nrn3897
NEUROPHYSIOLOGY
Under pressure Depolarization of LEPRexpressing neurons in the DMH is responsible for the increases in blood pressure that occur in mice with DIO
Diet-induced obesity (DIO) in both humans and rodents is associated with an increased risk of hypertension. The underlying molecular, cellular and hormonal mechanisms are not fully understood, but a new study by Simonds et al. suggests that obesity-induced elevation of circulating leptin increases blood pressure by acting on leptin receptors (LEPRs) specifically in the dorsomedial hypothalamus (DMH). Leptin is a hormone that is released into the bloodstream by adipose tissue, and it binds to LEPRs in the hypothalamus, leading to an increase in energy expenditure and a decrease in food intake. Leptin also increases blood pressure by increasing sympathetic nerve activity. Given that leptin secretion increases with weight gain, the authors examined whether this hormone might cause the increase
Jennie Vallis/NPG
in blood pressure observed in obese individuals. To do so, they fed mice a high-fat diet (HFD) so that the animals developed DIO. In each mouse, the increase in body weight was accompanied by an increase in the level of plasma leptin, and these changes were followed by a rise in blood pressure. However, mice lacking either leptin or LEPRs that were fed a HFD became even more obese than HFD-fed wild-type mice but did not show elevated blood pressure, suggesting a role for leptin in driving DIO-induced hypertension. The DMH is an area of the hypothalamus known to be involved in energy balance and to express LEPRs. To investigate whether this brain area has a role in mediating DIO-induced hypertension, the authors assessed the effects of either local injection of a LEPR antagonist into the DMH or knockdown of the LEPR selectively in the DMH of hypertensive DIO mice. They found that both treatments resulted in decreased systolic blood pressure, implicating a role for LEPRs in DIO hypertension. Furthermore, in brain slices taken from normal mice, around a third of DMH neurons expressing LEPRs responded to leptin application by depolarization and/or an increase in spontaneous action-potential firing. Moreover, the authors found that postsynaptically, leptin modulates intrinsic conductances in a subpopulation of DMH neurons, and possibly exerts indirect presynaptic effects to increase excitability of DMH neurons.
NATURE REVIEWS | NEUROSCIENCE
The authors tested whether similar effects occurred in vivo using a pharmacologically selective ion channel that could be expressed in and selectively activate or silence DMH neurons. Activation of DMH neurons in lean mice was sufficient to induce an increase in blood pressure, and inhibition of DMH neurons in hypertensive DIO mice reduced blood pressure. These data suggest that depolarization of LEPR-expressing neurons in the DMH is responsible for the increases in blood pressure that occur in mice with DIO. In humans, loss-of-function mutations in the gene encoding leptin cause severe and early-onset obesity. Comparing children who have leptin deficiencies with an agematched control group of equally obese children who have normal leptin levels, the authors found that the children with leptin deficiencies had lower systolic blood pressure. Children with a loss-of-function mutation in the gene encoding a LEPR also showed a decrease in systolic blood pressure, but this effect was less pronounced. In summary, these findings suggest that in both mice and humans, the hypertension observed in DIO is caused by increased activation of DMH neurons by obesity-related elevated leptin levels. Sian Lewis ORIGINAL RESEARCH PAPER Simonds, S. E. Leptin mediates the increase in blood pressure associated with obesity. Cell 159, 1404–1416 (2014)
VOLUME 16 | FEBRUARY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEUROPHYSIOLOGY
Under pressure Depolarization of LEPRexpressing neurons in the DMH is responsible for the increases in blood pressure that occur in mice with DIO
Diet-induced obesity (DIO) in both humans and rodents is associated with an increased risk of hypertension. The underlying molecular, cellular and hormonal mechanisms are not fully understood, but a new study by Simonds et al. suggests that obesity-induced elevation of circulating leptin increases blood pressure by acting on leptin receptors (LEPRs) specifically in the dorsomedial hypothalamus (DMH). Leptin is a hormone that is released into the bloodstream by adipose tissue, and it binds to LEPRs in the hypothalamus, leading to an increase in energy expenditure and a decrease in food intake. Leptin also increases blood pressure by increasing sympathetic nerve activity. Given that leptin secretion increases with weight gain, the authors examined whether this hormone might cause the increase
Jennie Vallis/NPG
in blood pressure observed in obese individuals. To do so, they fed mice a high-fat diet (HFD) so that the animals developed DIO. In each mouse, the increase in body weight was accompanied by an increase in the level of plasma leptin, and these changes were followed by a rise in blood pressure. However, mice lacking either leptin or LEPRs that were fed a HFD became even more obese than HFD-fed wild-type mice but did not show elevated blood pressure, suggesting a role for leptin in driving DIO-induced hypertension. The DMH is an area of the hypothalamus known to be involved in energy balance and to express LEPRs. To investigate whether this brain area has a role in mediating DIO-induced hypertension, the authors assessed the effects of either local injection of a LEPR antagonist into the DMH or knockdown of the LEPR selectively in the DMH of hypertensive DIO mice. They found that both treatments resulted in decreased systolic blood pressure, implicating a role for LEPRs in DIO hypertension. Furthermore, in brain slices taken from normal mice, around a third of DMH neurons expressing LEPRs responded to leptin application by depolarization and/or an increase in spontaneous action-potential firing. Moreover, the authors found that postsynaptically, leptin modulates intrinsic conductances in a subpopulation of DMH neurons, and possibly exerts indirect presynaptic effects to increase excitability of DMH neurons.
NATURE REVIEWS | NEUROSCIENCE
The authors tested whether similar effects occurred in vivo using a pharmacologically selective ion channel that could be expressed in and selectively activate or silence DMH neurons. Activation of DMH neurons in lean mice was sufficient to induce an increase in blood pressure, and inhibition of DMH neurons in hypertensive DIO mice reduced blood pressure. These data suggest that depolarization of LEPR-expressing neurons in the DMH is responsible for the increases in blood pressure that occur in mice with DIO. In humans, loss-of-function mutations in the gene encoding leptin cause severe and early-onset obesity. Comparing children who have leptin deficiencies with an agematched control group of equally obese children who have normal leptin levels, the authors found that the children with leptin deficiencies had lower systolic blood pressure. Children with a loss-of-function mutation in the gene encoding a LEPR also showed a decrease in systolic blood pressure, but this effect was less pronounced. In summary, these findings suggest that in both mice and humans, the hypertension observed in DIO is caused by increased activation of DMH neurons by obesity-related elevated leptin levels. Sian Lewis ORIGINAL RESEARCH PAPER Simonds, S. E. Leptin mediates the increase in blood pressure associated with obesity. Cell 159, 1404–1416 (2014)
VOLUME 16 | FEBRUARY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
