Leptin Is Not Essential for Obesity-Associated Hypertension

BACKGROUND AND OBJECTIVE: Hyperleptinemia is supposed to play a causal role in the development of obesity-associated hypertension, possibly via increased sympathetic tone. Hence patients with congenital leptin deficiency should be hypotensive and their low blood pressure should increase under leptin substitution. SUBJECTS AND METHODS: To test this assumption, we examined ambulatory blood pressure, resting heart rate, Schellong test results, cold pressor test results, heart rate variability, catecholamine metabolites, and aldosterone levels in 6 patients with congenital leptin deficiency before as well as 2-7 days and 7-14 months after the start of leptin substitution. Ambulatory blood pressure was also examined in 3 patients with biallelic disease-causing variants in the leptin receptor gene. RESULTS: Contrary to our expectations, even before leptin substitution, 1 patient with biallelic leptin receptor gene variants and 4 patients with leptin deficiency had been suffering from hypertension. Short-term substitution with leptin increased blood pressure further in 3 out of 4 patients (from 127.0 ± 11.7 to 133.8 ± 10.6 mm Hg), concomitant with an increase in resting heart rate as well as in heart rate during the Schellong test in all patients (from 87.6 ± 7.7 to 99.9 ± 11.0 bpm, p = 0.031, and from 102.9 ± 13.5 to 115.6 ± 11.3 bpm, p = 0.031, respectively). Furthermore, the systolic blood pressure response during the cold pressor test increased in 4 out of 6 patients. Unexpectedly, catecholamine metabolites and aldosterone levels did not increase. After long-term leptin substitution and weight loss, the resting heart rate decreased in 4 out of 6 patients compared to baseline, and in all patients below the heart rate seen immediately after the start of therapy (from 99.9 ± 11.0 to 81.7 ± 5.4 bpm; p = 0.031). CONCLUSIONS: These results show that obesity-associated hypertension does not depend on the presence of leptin. However, short-term leptin substitution can increase the blood pressure and heart rate in obese humans with leptin deficiency, indicating that leptin plays at least an additive role in obesity-associated hypertension. The mechanisms behind this are not clear but might include an increase in regional sympathetic tone.