Weight gain and hypertension

With conventional thinking, body weight gain causes hypertension. This concept is based on a large body of evidence linking weight gain to increases in blood pressure, including (i) population studies indicating that being overweight or obese are major risk factors for development of hypertension [1]; (ii) observation studies showing that weight gain increases blood pressure [2]; and (iii) clinical studies demonstrating that weight loss lowers blood pressure in most hypertensive patients [3]. In addition, epidemiological studies suggest that up to 75% of the risk for hypertension is attributable to excess weight [4]. By contrast to conventional thinking, there are a limited number of reports suggesting that the development of hypertension precedes weight gain. For example, in the Framingham Study, among subjects who were weight-matched at baseline, subjects with higher blood pressure subsequently gained more weight than subjects with lower baseline blood pressure [5]. Similarly, in the Tecumseh Study, hypertensive adults showed elevated blood pressure values as young children, but only later became overweight [6]. Both studies indicate that, in some patients, increases in blood pressure occur before increases in body weight. Is sympathetic activation the ‘missing link’ between overweight and hypertension? It is generally agreed that obesity and hypertension are linked through activation of the sympathetic nervous system. Studies based on the assay of circulating catecholamine levels [7], measurement of systemic or regional norepinephrine spillover [8,9] and direct recording of efferent postganglionic muscle sympathetic nerve traffic [7,10–12] have consistently demonstrated independent but additive increases in sympathetic activity related to being overweight and/or to having high blood pressure. Traditionally, obesity-related hypertension has been attributed, in part, to weight-related increases in sympathetic activity, which is then purported to cause or worsen hypertension. Based in part on the observations from Framingham and Tecumseh, Julius et al. [13] suggested a contrary hypothesis, where increased sympathetic activity results in a down-regulation of β-adrenergic receptors, thereby resulting in a decreased thermogenic response and thus an increased propensity to gain weight. In other words, chronic sympathetic hyperactivity associated with hypertension leads to weight gain as opposed to weight gain causing sympathetic activation. In the current issue of the journal, Valentini et al. [14] tested the hypothesis that β-adrenergic-mediated thermogenesis is impaired in hypertensive individuals. Haemodynamic, metabolic, and thermogenic responsiveness to β-adrenergic stimulation (systemic isoproterenol infusion) was significantly reduced in 13 hypertensive subjects compared to 25 normotensive control subjects. Heart rate responses and increases in energy expenditure were attenuated in the hypertensive subjects and negatively correlated with urinary norepinephrine. From these findings, Valentini et al. [14] conclude that a generalized decrease of β-adrenergic responsiveness takes place in hypertensive subjects, in support of the concept that ‘… sympathetic overactivity, via downregulation of beta-adrenoceptor mediated thermogenic responses, facilitates the development of obesity in hypertension'. Consistent with the original hypothesis of Julius et al. [13], the current results are provocative in suggesting that obesity is a consequence as opposed to a cause of sympathetic activity. If this is the case, it redefines sympathetic hyperactivity as a cause of both hypertension and weight gain, and establishes a paradigm whereby sympathetic overactivation leads to hypertension and weight gain, with weight gain further worsening the hypertension. Sympathetic modulation of thermogenesis The sympathetic nervous system plays a crucial role in energy metabolism primarily through regulation of the resting metabolic rate, which accounts for 50–70% of adult energy expenditure [15]. Microneurographic nerve traffic recordings [16], urinary norepinephrine and norepinephrine spillover studies [17,18], and power spectral analysis of heart rate variability [19] indicate a strong relationship between resting metabolic rate and sympathetic nervous system activity. The sympathetic nervous system modulates thermogenesis through stimulation of β-adrenergic receptors. β-adrenergic responsiveness has been shown to be reduced in hypertensive subjects as suggested, among other findings, by attenuated heart rate responses to β-adrenergic agonists [20]. The current study by Valentini et al. [14] extends these observations by demonstrating that reduced β-adrenergic responsiveness in hypertension also manifests as reduced energy expenditure, which would tend to promote weight gain. Thus, the findings of Valentini et al. [14] link diminished β-adrenergic responsiveness to weight gain in hypertensive subjects. Such a relationship is supported by clinical experience with β-blocking agents causing weight gain [21], presumably, although not univocally [22], secondary to suppression of thermogenesis. Central to the hypothesis that sympathetic overactivity promotes weight gain is the assumption that chronic sympathetic activation downregulates or desensitizes β-adrenergic receptor responsiveness. Although diminished β-adrenergic responsiveness in hypertensive subjects is well demonstrated, and some studies suggest that it is related to prolonged over-stimulation [23], such a cause/effect relationship lacks definitive elucidation. An alternative explanation may be that alterations in β-adrenergic receptor function, either acquired or genetic, result in diminished receptor responsiveness, with a consequential reflex increase in sympathetic neural drive. In this scenario, weight gain is attributable to blunted β-adrenergic responsiveness secondary to inherent receptor dysfunction, as opposed to sympathetic overactivity. Study limitations As acknowledged by Valentini et al. [14], their study faces some intrinsic limitations. For example, some of the study conclusions are based on heart rate changes to isoproterenol administration, taken as indices of cardiac adrenergic drive. However, it should be emphasized that heart rate has been shown to have a limited relationship with more direct indices of adrenergic drive such as plasma norepinephrine or muscle sympathetic nerve traffic not only at rest, but also during pharmacologic challenge [24,25], implying that this haemodynamic variable cannot be considered as a faithful marker of adrenergic cardiovascular drive. Furthermore, the study by Valentini et al. [14] is limited by hypertensive subjects being significantly heavier than the normotensive control subjects. A better test of the hypothesis would have involved a comparison of β-adrenergic-mediated energy expenditure in weight-matched hypertensive and normotensive subjects. However, as conducted by Valentini et al. [14], their study does not fully address the pivotal question of which comes first: weight gain or sympathetic overactivation. Failure to weight-match their subjects presumably reflects the difficulty of finding hypertensive subjects with primary hypertension who are not overweight, and emphasizes the importance of understanding why hypertension and obesity so commonly coexist.