Sympathetic Drive as a Determinant of Weight Loss Intervention Outcome: Strengths and Limitations

Weight loss interventions are frequently characterized by an unsatisfactory and a depressing success rate. Their more common unfavorable outcomes are represented by the patient's inability to lose weight or by the occurrence of the so-called “weight cycling” phenomenon, characterized by a rapid regain of the weight lost in the initial phases of the therapeutic approach.

The intriguing article by Masuo et al¹ published in this issue of the Journal attempts to identify the factors potentially responsible for the phenomenon, with obvious important clinical implications. By making use of an accurate and a carefully planned experimental study's design, the investigators followed overweight individuals throughout a 2-year period during which weight loss interventions were performed in conjunction with measurements of hemodynamic, anthropometric, and neurometabolic (leptin, insulin, norepinephrine) variables. Weight loss–resistant and sensitive subjects were then identified and the relationships with the various parameters carefully performed. The main study finding is that the major determinants of the weight loss outcome are represented by the baseline (ie, preintervention) values of body fat mass, leptin, and circulating norepinephrine values. In practical terms, these results mean that individuals with higher body mass, leptin, and norepinephrine take greater benefits from the weight loss programs, virtually not experiencing any resistance to the weight loss interventions or weight rebound phenomena.

As frequently happens even with excellent clinical investigations, the study's results cannot be considered conclusive, opening the door to new and intriguing questions. For example, do the results apply to truly “obese” subjects rather than only to overweight individuals? The question has obvious clinical relevance, given the demonstration that obese rather than overweight subjects are the individuals who experience, to a greater extent, weight loss resistance and regain. In addition, are the data in any way affected by the anatomical distribution of body fat? In other words, do the data apply to patients with visceral body fat depots or to subjects with peripheral obesity? It is likely that results might be different according to the body fat distribution because, compared with peripheral obesity, visceral obesity displays 1) greater levels of insulin resistance, 2) greater values of leptin, and 3) greater degrees of sympathetic activation.² It should thus be expected that in this latter type of obesity the relation between leptin and norepinephrine with the weight loss outcomes should be stronger and more evident.

Two other features of the study deserve to be highlighted. First, the investigators did their best to rule out the participation of confounding factors in the study results. However, they could not exclude that the study's findings were somehow affected by the presence or absence of the sleep apnea syndrome, which Masuo et al investigated only via the anamnestic approach rather than via the more specific and sensitive polysosomnographic evaluation.¹ It is likely that the presence of sleep apnea may also have affected the results, by directly interfering with the weight loss outcomes as well as with the sympathetic activation.^3,4 Finally, as properly emphasized by the investigators, assessment of adrenergic drive was based in the present study on plasma norepinephrine assay, that is, on a technique easy to performed but unable to determine whether the sympathetic overactivity has a central, peripheral, or reflex origin.⁵ The lack of a correlation between plasma norepinephrine and heart rate speaks against a reflex origin of the neuroadrenergic abnormality, leaving, however, the other two hypotheses unanswered.