Leptin's actions in the Dorso Medial Hypothalamus; the cause of hypertension in obesity? — ASN Events
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  3. Leptin's actions in the Dorso Medial Hypothalamus; the cause of hypertension in obesity?

Leptin's actions in the Dorso Medial Hypothalamus; the cause of hypertension in obesity? (#27)

Stephanie E Simonds 1 , Russell D Brown 1 , Ralph DiLeone 2 , Jaspreet Bassi 3 , Andrew M Allen 3 , Pablo J Enriori 1 , Scott M Sternson 4 , Eric Ravussin 5 , Steve P O'Rahilly 6 , Frank Greenway 5 , Kevin L Grove 7 , Sadaf Farooqi 6 , Michael A Cowley 1
  1. Monash University, Clayton, Vic, Australia
  2. Yale University, New Haven, usa
  3. Melbourne University, Melbounre, Australia
  4. Janelia Farm Research Campus , Howard Hughes Medical Institute, Ashburn, Virginia, USA
  5. Nutrition Obesity Research Center, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
  6. Cambridge University, Cambridge, UK
  7. Oregon Primate centre, Oregon, USA

Cardiovascular diseases (CVDs) are the number one cause of death globally. Obesity increases the risk of Cardiovascular diseases. Plasma leptin concentration is elevated in obesity and leptin can increase sympathetic nerve activity (SNA). Chronically elevated SNA can cause hypertension. In C57Bl/6J mice hypertension developed after 12 weeks of high fat feeding (HFF), once plasma leptin levels had risen. After 20 weeks of HFF, diet induced obese mice (DIO) were tachycardic and hypertensive, with elevated leptin levels compared to controls fed a chow diet. 20 week chow fed Leptin-deficient (ob/ob), and leptin receptor (LepR)-deficient (db/db) mice were normotensive and not tachycardic in spite of morbid obesity, HFF also didn’t cause the development of hypertension in these genetically modified mice. Leptin strongly correlated with body fat, blood pressure (BP) and heart rate (HR) in C57Bl/6J mice. Human subjects exhibit a similar trend, with leptin deficient and lepR deficient human subjects having significantly lower BP compared to BMI and aged matched controls. Exogenous leptin significantly elevated BP and HR, despite significantly reducing bodyweight and food intake in ob/ob mice. Peripheral neutralization of leptin, using a leptin antibody significantly reduced HR and BP. Central antagonism (lepR antagonist ICV) of the LepR reduced both HR and BP in DIO mice. The Dorso medial hypothalamus (DMH) remains leptin responsive in DIO mice. Blockade of leptin signalling with either a LepR antagonist, viral knockdown (AAV) or Designer receptors exclusively activated by designer drugs (DREADS) system inhibiting neurons expressing LepR specifically in the DMH normalized the elevated BP of DIO mice. In lean normotensive mice, activation (via DREADS) of DMH lepR expressing neurons elevates BP. This research demonstrates that leptin is a major contributor to hypertension in obesity through actions initiated in the DMH. These DMH lepR neurons could be a potential therapeutic target for the long term resolution of elevated BP in obesity.

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