225 IF LEPTIN IS THE CULPRIT, IS ESTROGEN THE ANTAGONIST IN OBESITY ASSOCIATED HYPERTENSION?

Abstract

Obesity increases the risk of hypertension and cardiovascular diseases developing. Our research shows that elevated leptin levels are essential in development of obesity associated hypertension. Obese leptin deficient children have significantly(p<0.01) lower blood pressure(BP) compared to weight and aged matched subjects. Obese male mice fed a high fat diet(HFD) are hypertensive(113.7±1.1mmHg) and tachycardic(577.5±4.8BPM) compared to weight matched leptin deficient(ob/ob:100.7±3.0mmHg,510±7.0BPM) and leptin receptor deficient db/db:103.5±1.7mmHg,519.7±8.0BPM) mice measured via radiotelemetry. The Dorso Medial Hypothalamus(DMH) region in the brain is critical for obesity associated hypertension as blocking leptin actions here with both a leptin receptor antagonist or Adeno Associated Viral/shRNA knockdown of DMH leptin receptors reduces the elevated BP. Female mice fed HFD develop metabolic syndrome, including insulin insensitivity and hypertension much slower compared to males, despite leptin levels in females being substantially higher per each gram of body fat. Why are females protected? Unlike female mice, obese male mice fed a HFD have (p<0.01) higher sympathetic nerve activity (SNA) indirectly measured as brown adipose tissue temperature(36.73±0.1°C) compared to lean male mice(35.96±0.1°C) and this is leptin driven. In female mice thermogenesis is significantly(p<0.05) increased once mice have all endogenous estrogen removed, via ovariectomy. Ovariectomized female mice that have been replaced with exogenous estrogen have significantly lower thermogenesis, most likely driven by reduced SNA. Interestingly every neuron expressing estrogen receptors in the hypothalamus(the region including the DMH) also expresses a leptin receptor. While leptin increases SNA in obesity, estrogen may counteract leptin's actions through neurons in higher brain regions, decreasing SNA and protecting from the development of hypertension.