Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Abstract

ObjectiveHypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc−/−) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc−/− mice could explain their elevated glycosuria and consequent enhanced glucose tolerance.MethodsWe measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc−/− mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc−/− mice or the renal-denervated mice.ResultsConsistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc−/− mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc−/−, WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc−/− mice.ConclusionHence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.

Differential contribution of POMC and AgRP neurons to the regulation of regional autonomic nerve activity by leptin

“…Renal SNA has also emerged as a key contributor to glucose homeostasis through the control of glucose excretion in the urine. For instance, reduced renal SNA appears to account for the elevated glycosuria and subsequent improved glucose tolerance in mice bearing hypothalamic-restricted loss of the pomc gene [42] . However, the contribution of LepR on POMC neurons to the regulation of urinary glucose excretion is not known, but is worth investigating.…”

Renal injury in Seipin ‐deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue‐kidney crosstalk

“…A study has shown that hypothalamic arcuate nucleus-specific proopiomelanocortin-deficient mice exhibit elevated glycosuria and electrolyte excretion, normoglycemia, increased food intake, IR, and glomerular hypertrophy. The study found renal GLUT2 but not SGLT2 levels decreased via reduced renal sympathetic nerve activity (46,47). Interestingly, Seipin expression is evident in the arc of hypothalamus (48).…”

Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation

“…Thereby, they can adapt numerous processes in the integrated regulation of whole-body metabolism, including control of hepatic glucose metabolism and VLDL secretion, BAT activation, and adipose tissue lipolysis, (Balthasar et al, 2004; Berglund et al, 2012; Kőnner et al, 2007; Parton et al, 2007; Ruud et al, 2017; Scherer et al, 2011, 2016; Shin et al, 2017; Steculorum et al, 2016). Importantly, POMC neurons have been demonstrated to promote sympathetic nerve activation in response to leptin and insulin (i.e., in control of SNA in various tissues) (Bell et al, 2018; Chhabra et al, 2017; Chitravanshi et al, 2016; Rahmouni et al, 2003). Although our experiments clearly reveal that chemogenetic POMC neuron activation is sufficient to rapidly induce hepatic SNA and that optogenetic POMC neuron activation promotes S6 phosphorylation and Xbp1 splicing, they do not rule out the possibility that the concomitant inhibition of AgRP neuron activity may also contribute to these effects upon sensory food perception.…”