Since the pioneering paper by Zhang et al.  published in Nature exactly 20 years ago, a consistent body of information has been collected on leptin and its interactions with the sympathetic nervous system and blood pressure values. However, as recently emphasized by Allyn Mark  in the Carl Ludwig Memorial lecture held at the American Physiological Society, evidence comes largely from animal studies, whereas human data are frequently lacking and the ones available are often controversial. To briefly summarize the state-of-the-art knowledge in humans on this issue, the key information can be schematically recalled as follows.
First, systemic administration of leptin in human beings does not seem to affect the neuroadrenergic cardiovascular drive . When in the minority of the published studies some effect is detectable, leptin appears to exert sympathoexcitatory influences at least in the short-term period . No study, however, has so far been performed with the aim of establishing the dose–response effects of exogenous leptin on human adrenergic neural function. A further element of uncertainty is whether the behaviour of the adrenergic nervous system during leptin infusion is paralleled by a similar behaviour of blood pressure values. This is because many studies do not report information on blood pressure and the few that include blood pressure values do not show any consistent effect. Second, in correlation studies plasma leptin levels have been documented to show some direct relationships with indices of sympathetic activity, such as renal norepinephrine spillover  or efferent postganglionic muscle sympathetic neural discharge in the peroneal nerve . However, some reports failed to show such a relationship particularly when healthy normoweight individuals, and not obese individuals in which both the sympathetic and the leptin systems are activated, were examined . Surprisingly, but in line with what it has been reported for the already mentioned studies looking at the effects of exogenous administration of leptin, missing is the information available in these studies on the correlation between plasma leptin and resting blood pressure values. Finally, in genetic human models of leptin deficiency, sympathetic neural function displays a reduction . The inconsistent data available on blood pressure also in these studies again prevent any sound conclusion to be drawn as to whether and to what extent the decrease in sympathetic neural drive can affect this haemodynamic variable.
The data by Pieterse et al. , published in the present issue of the Journal, have to be analysed and discussed in the context of this scanty and conflicting information. The results refer to a sub-analysis of the data collected within the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study, which has already provided a series of remarkable information on the behaviour of the sympathetic neural function in African versus Caucasian men and women. The novel data of the present sub-analysis  include the evidence that compared with Caucasians, Africans are characterized by a low frequency-to-high frequency ratio of the heart rate signal suggestive of a sympathetic overdrive; the adrenergic activation is accompanied by an hyperleptinemic state; in African men, leptin shows an independent direct correlation with renin and night-time heart rate, whereas it shows an inverse one with heart rate variability total power and triangular index and in Caucasian men and women, leptin values display significant and direct correlations with 24-h day-time and night-time heart rate, whereas heart rate variability index and total power showed an inverse relationship. These findings allowed the authors to conclude that plasma leptin is associated with adrenergic markers and that this association is independent of a number of confounders, including BMI.
Although the study by Pieterse et al.  contributes to our understanding of the complex relationships between leptin and autonomic drive by providing new insights based on a large and solid database, a number of considerations have to be done highlighting some problems emerging from the SABPA sub-analysis.
As already mentioned, the SABPA study has provided during the years a number of important information on the behaviour of the adrenergic neural drive in Africans. Those more closely related to the present findings are represented by the finding that Africans display a hyper-reactivity to manoeuvres capable to activate the sympathetic nervous system, such as cold pressor test  and an impaired baroreflex control of the cardiovascular system . These two observations therefore fit quite well with the finding, provided by the present study, that in the South African population recruited by the SABPA study, the power spectral analysis of heart rate signals documents a higher low-frequency and a lower high-frequency spectral component, indicating an augmented sympathetic and a reduced parasympathetic modulation of the heart rate signal. The question, however, is whether and to what extent this finding indicating an adrenergic overdrive is specific for the cardiac organ or it can be generalized to the entire cardiovascular system. In other words, the question arises as to whether data collected throughout power spectral data of heart rate can be representative of the sympathetic drive in other cardiovascular districts and thus of the adrenergic drive of the circulation as a whole. Unfortunately, the evidence available does not speak in favour of this latter possibility. This is because it has been previously shown that in physiological and pathological conditions characterized by a marked sympathetic activation, such as the aging process and congestive heart failure, power spectral analysis of the heart rate signal is unable to pick up any adrenergic overdrive . This was evident despite the marked increase in cardiac norepinephrine spillover and sympathetic nerve firing rate concomitantly documented by the norepinephrine radiolabelled technique and the microneurographic nerve traffic recording in the two above-mentioned conditions . In addition, in an above-mentioned study , leptin values showed a correlation with heart rate, taken as an index of cardiac adrenergic drive, but not with muscle sympathetic nerve traffic, that is a variable well recognized as being a sensitive marker of the overall adrenergic cardiovascular drive . Thus, it remains to be proven by approaches capable of directly assessing sympathetic neural function, such as norepinephrine spillover, microneurography or power spectral analysis of the blood pressure signal, that in Africans, markers representative of the overall adrenergic drive are activated. The same consideration should be applied for the conclusion on the basis of findings that 24-h daytime and night-time heart rate displays a relationship with leptin, and that sympathetic activity and leptin are related with each other. This is because heart rate is only a pale marker of adrenergic drive which does not necessarily prove a relationship with a direct index of adrenergic cardiovascular drive, such as efferent postganglionic sympathetic nerve traffic, in several clinical models of sympathetic activation .
A final argument to be briefly addressed in analysing the SABPA data refers to the fact that, as already mentioned in discussing the limitations of the previously published studies, in the study by Pieterse et al. , no mention exists of the blood pressure data that have been collected in the Caucasian and African population screened. In this specific study, the lack of such information is of particular relevance, given the fact that the authors performed not only clinic but also ambulatory blood pressure monitoring. The analysis of such data would have allowed to assess for the first time whether and to what extent leptin values are related to 24-h blood pressure load and its variability spectral components in a population sample with elevated leptin levels. Indeed, at variance from spectral analysis of heart rate, the blood pressure spectral data are related to direct indices of adrenergic drive , and thus they would have provided important insights on the leptin–sympathetic relationships.
In conclusion, what has been discussed in this editorial commentary represents the pathophysiological background for future studies in the hope that the questions that still remain unaddressed will find convincing and documented answers in the next years.
Conflicts of interest
There are no conflicts of interest.
1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature
2. Mark AL. Carl Ludwig distinguished lectureship award from the neural control and autonomic regulation (NCAR) section, 2011-Selective leptin resistance revisited. Am J Physiol
3. Mackintosh RM, Hirsch J. The effects of leptin administration in nonobese human subjects. Obes Res
4. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest
5. Eikelis N, Schlaich M, Aggarwal A, Kaye D, Esler M. Interactions between leptin and the human sympathetic nervous system. Hypertension
6. Snitker S, Pratley RE, Nicolson M, Tataranni PA, Ravussin E. Relationship between muscle sympathetic nerve activity and plasma leptin concentration. Obes Res
7. Narkiewicz K, Kato M, Phillips BG, Pesek CA, Choe I, Winnicki M, et al. Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects. J Hypertens
8. Pieterse C, Schutte R, Schutte AE. Autonomic activity and leptin in Africans and whites: the SABPA study. J Hypertens
9. Reimann M, Hamer M, Schlaich MP, Malan NT, Ruediger H, Ziemssen T, Malan L. Greater cardiovascular reactivity to a cold stimulus is due to higher cold pain perception in black Africans: the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. J Hypertens
10. Van Lill L, Malan L, van Rooyen J, Steyn F, Reimann M, Ziemssen T. Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: the SABPA study. Blood Press
11. Kingwell BA, Thompson JM, Kaye DM, McPherson GA, Jennings GL, Esler MD. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation
12. Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens
13. Grassi G, Vailati S, Bertinieri G, Seravalle G, Stella ML, Dell’Oro R, Mancia G. Heart rate as marker of sympathetic activity. J Hypertens
14. Pagani M, Montano N, Porta A, Malliani A, Abboud FM, Birkett C, Somers VK. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation