A Novel Role for Hindbrain Astrocytes in Leptin‐Mediated Energy Balance and the Development of Obesity
Authors: Stein Lauren , Lhamo Rinzin , Corini Alexis , Cao Anh , Chen Jack , Hayes Matthew 
Published: June 2021

There now exists an appreciation for the role of glial cells as active participants in the neuroendocrine control of appetite and energy balance. The adipocyte‐derived anorectic hormone leptin acts directly on astrocytes to modify their morphology, interactions with metabolic neuronal circuitry, and the ability to modulate to synaptic glutamate levels. Further, high fat diet (HFD)‐induced obesity results in astrogliosis (abnormal proliferation and function) with concurrent upregulation of the leptin receptor expression, suggesting that astrocytes may contribute to the pathological development of obesity and leptin resistance. The finding that the leptin receptor is expressed on astrocytes within the nucleus tractus solitarius (NTS), a critical site for energy balance control, offers the intriguing possibility that this glial population is a critical component in leptin‐mediated energy balance. Therefore, we sought to examine the role of NTS astrocytes in mediating the intake and body weight suppressive effect leptin and whether this serves as an additional site of obesity‐induced maladaption. Adult male and random‐cycling female Sprague‐Dawley rats maintained on either a chow or HFD (n=10–12/sex) were surgically implanted with an indwelling 4th ventricle cannula for intracerebroventricular (icv) drug administration. At dark onset, overnight food deprived rats were pretreated with the astrocyte‐specific inhibitor fluorocitrate (FC; 5 nmol) or vehicle, immediately followed by 5 μg/μL leptin or vehicle. Food intake and body weights were recorded at 1, 3, 6, and 24 hours post treatment. In chow‐fed males, but not females, FC pretreatment attenuated both the hypophagia and body weight reduction produced by central leptin administration. HFD‐fed male and female rats exhibited a diminished anorectic response to leptin administration alone, for which FC pretreatment had no effect. These findings suggest that inhibition of astrocyte activity attenuates the ability of NTS leptin receptor activation to promote negative energy balance in a diet‐dependent manner as well as sex‐related difference in the neural‐glial interactions underlying this effect. Next, to determine whether HFD‐induces hindbrain astrogliosis, male (n=6/diet) and female (n=5/diet) rats were placed on either a chow or HFD for 4 weeks, then transcardially perfused and brains harvested for immunohistochemical analysis. In males, but not females, chronic HFD exposure resulted in astrogliosis within the NTS as indicated by a significant increase in glial‐fibrillary acidic protein (GFAP) immunoreactivity. Collectively, these findings provide novel evidence for NTS astrocytes in leptin‐mediated control of energy balance and a potential contributor to the development of obesity. Ongoing experiments are focused on elucidating the functional relevance of NTS astrocyte‐derived leptin signaling on metabolic homeostasis. Importantly, a future line of research will investigate the underlying mechanisms governing the observed sexual dimorphism in astrocytic regulation of energy balance.Support or Funding InformationNIH NIDDK R01‐DK096139This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.