Astroglial Regulation of Caloric Intake Following Acute High‐Fat Diet Exposure

Abstract

Obesity and long‐term exposure to high fat diet (HFD) are both associated with peripheral and central inflammation. Acute HFD exposure, however, is also associated with neuroinflammation in brainstem areas responsible for control of gastric functions and energy homeostasis prior to the development of obesity. Neuroinflammation and astroglial activation are known to modulate neuronal activity and physiological outcomes, such as gastric motility, emptying, and food intake. Following initial HFD exposure and a brief (24hr) period of hyperphagia, both humans and rodent models regulate their caloric intake within 3–5 days. The neuroinflammation observed within the brainstem during acute HFD exposure may, therefore, contribute to the homeostatic regulation of caloric intake. The aim of this study is to test the hypothesis that restoration of energy balance during acute HFD exposure requires brainstem astroglial activation.Sprague‐Dawley rats, 6–8 weeks of age, were fed a control or HFD (14% or 60% kcal from fat, respectively) throughout the study. Immunohistochemical techniques were used to examine astrocyte (GFAP and S100β) and microglia (Iba1 and CD11b) morphology and activity state within the dorsal vagal complex (DVC) after 1,3,5, and 14 days of HFD exposure. Confocal microscopy was used to quantify astrocyte and microglial density, staining intensity, and morphology. Chronic 4th ventricular cannulae were implanted for the administration the astrocyte metabolism inhibitor, fluoroacetate, the microglial activation inhibitor, minocycline (5 and 10mg/mL in 5μL, respectively), or vehicle (PBS) to assess the role of astrocytes and microglia in the regulation of caloric intake. Food intake and body weight were measured twice daily for 10 days prior to, and throughout, HFD exposure. The effects of 4th ventricular administration of fluoroacetate on gastric emptying rates were additionally assessed using the 13C octanoic acid breath test technique.Immunohistochemical characterization of DVC microglia and astrocytes demonstrated an increase in Iba1 and GFAP staining intensity on days 3 and 5 of HFD exposure, which recovered by day 14 (3 Day: 225%, 210%, 5 Day: 195%, 280%, 14 Day: 124%, 92% of control total fluorescence (CTF), respectively, N=2). 4th ventricular application of fluoroacetate and minocycline attenuated the homeostatic regulation of caloric intake observed following acute HFD exposure, compared to vehicle controls (AUC: 242±11.4 vs. 264±2.8 vs. 187±10.6, P<0.05 F=10.35, N=3–5) and preliminary data suggest that fluoroacetate also attenuates the homeostatic delay in gastric emptying observed in control conditions (t1/2: 102.5% vs 150.3% of baseline, respectively, N=1–2).The results from this study indicate that astrocyte and microglial activation occurs within 3–5 days of HFD exposure and is required for the homeostatic regulation of caloric intake and gastric emptying following acute HFD exposure. Understanding the physiological mechanisms responsible for energy homeostasis, and importantly, how this mechanism is lost, is critically important for the development of novel therapeutic targets for the treatment of obesity.Support or Funding InformationAPS UGSRF to CSNIH DK111667 to KNB NIH F31 118833 to CC