Your fat talks to your brain through your kidneys

This editorial concerns a paper, published in the current issue of the journal, providing evidence of an as yet unsuspected mechanism by which obesity can alter autonomic control of the cardiovascular system (Khan et al. 2015). It is now well established that obesity leads to activation of the sympathetic nervous system, which is in turn a major driver in the pathogenesis of obesity-related hypertension (Hall et al. 2015). Many of the pathways that drive activation of the sympathetic nervous system in obesity have been identified. Chief among these are thought to be pathways activated by leptin within the hypothalamus. Khan et al. (2015) now provide evidence that obesity can alter input from renal afferents that influence baroreceptor control of the circulation. The authors found that the sensitivity of arterial baroreflex control of heart rate and renal sympathetic nerve activity (RSNA) was greatly blunted in rats with diet-induced obesity. The reduction in RSNA normally observed in response to acute expansion of extracellular fluid volume was also greatly blunted by obesity, indicating altered control of RSNA by so-called low pressure baroreceptors. These findings confirm and extend previous observations of altered baroreceptor function in obesity (see Khan et al. 2015 for references). The truly startling finding in this study was that the effects of obesity on baroreflex function were almost completely abrogated by acute bilateral renal denervation. These findings suggest that, in obesity, signals from renal afferents blunt the function of baroreceptor reflexes. They therefore have important implications for the potential use of renal denervation as a therapeutic modality in obesity-associated hypertension. But for we physiologists, they also point to a potentially rich new field of study of a previously unsuspected mechanism through which obesity can alter autonomic function. What potential mechanisms might explain the findings of Khan and colleagues? The authors refrained from speculation regarding this question, but I have no qualms about doing so in this editorial. It is well established that renal afferent nerve traffic can alter the activity of the autonomic nervous system. Thus, the most germane question is, how does obesity activate renal afferent nerves? I see at least three candidate mechanisms. Increased visceral and retroperitoneal fat mass can increase intra-abdominal pressure and renal interstitial hydrostatic pressure (Hall et al. 2015). Increased renal hydrostatic pressure has been shown to acutely activate neurones within the dorsal horn of the thoracic spinal cord (Fitch et al. 1997). The observations of Khan et al. were made in rats in which the kidneys had been exposed by flank incisions rather than an abdominal incision, so intra-abdominal pressure was unlikely to have been greatly altered by their surgical procedures. Thus, a reflex pathway arising from pressure-sensitive receptors in the renal parenchyma remains a possible candidate mechanism to explain their findings. One approach to further investigate this proposition would be to perform similar experiments in rats subjected to laparotomy and/or removal of the renal capsule. Obesity in some species is also associated with accumulation of ectopic fat, including within the renal pelvis, which can obstruct urine flow. Renal mechanoreceptors can also be activated by increased ureteral pressure (Kopp et al. 1985). However, fat accumulation in the kidney appears not to be a major characteristic of obesity in rats (Hall et al. 2015), so this reflex pathway appears unlikely. There is evidence that, in a number of models of chronic kidney disease, ischaemia and/or hypoxia within the kidney may activate renal afferents (see Evans et al. 2013). For example, Khan et al., in a study of similar design to that of their current report, showed that renal denervation could restore baroreflex control of RSNA and heart rate in a rat model of renal failure induced by cisplatin (Khan et al. 2014). However, the rodent model of obesity studied by Khan et al. was not associated with apparent renal ischaemia or deficits in creatinine clearance, so it could hardly be considered a model of chronic kidney disease (Khan et al. 2015). Thus, the mechanistic relationship between their current (Khan et al. 2015) and previous (Khan et al. 2014) findings remains enigmatic. Nevertheless, I am not aware of previous studies in which renal oxygenation, or other chemical factors that might be expected to alter activation of renal afferents, has been assessed in a rodent model of obesity. In the light of the current findings of Khan et al., such studies are warranted. An important characteristic of obesity is the altered circulating levels of insulin and adipokines such as leptin and adiponectin, together with activation of the renin–angiotensin system and the sympathetic nervous system (Hall et al. 2015). Leptin can activate sensory nerves within white adipose tissue to activate the sympathetic nervous system (Tanida et al. 2000), but I am not aware of any evidence that it can activate renal sensory nerves. Therefore, studies of the effects of adipokines on afferent renal nerve activity are warranted. Another possible explanation for the findings of Khan et al. is that obesity enhances the sensitivity of baroreflex pathways in the central nervous system to renal afferent input. That is, it might not be that the kidney is talking louder to the brain, but that the brain is listening more intently. Certainly, this proposition is consistent with the lack of effect of renal denervation on baroreflex control of the circulation in lean animals, as well as the marked effect of renal denervation in obese animals. It is also consistent with the strong evidence of altered central control of sympathetic drive in obesity (How et al. 2014). As acknowledged by the authors, an important limitation of their study was that it was performed in anaesthetised rats. Their findings are potentially very important, both in terms of therapeutic approaches in obesity-associated hypertension and our understanding of the physiology of renal afferents. Thus, further studies in unanaesthetised animals are warranted, despite the methodological challenges they pose. The new findings of Khan et al. raise many more questions than they answer, as all good science should. Their work should stimulate further work in the field. In this respect, I hope my speculative musings might be of some help. The author has no relevant conflict of interests.