Hindbrain Cocaine- and Amphetamine-Regulated Transcript Induces Hypothermia Mediated by GLP-1 Receptors

Abstract

Cocaine-and amphetamine-regulated transcript (CART) peptides are widely distributed throughout the neuraxis, including regions associated with energy balance. CART's classification as a catabolic neuropeptide is based on its inhibitory effects on feeding, coexpression with arcuate nucleus proopiomelanocortin neurons, and on limited analysis of its energy expenditure effects. Here, we investigate whether (1) caudal brainstem delivery of CART produces energetic, cardiovascular, and glycemic effects, (2) forebrain-caudal brainstem neural communication is required for those effects, and (3) glucagon-like peptide-1 receptors (GLP-1Rs) contribute to the mediation of CART-induced effects. Core temperature (Tc), heart rate (HR), activity, and blood glucose were measured in rats injected fourth intracerebroventricularly with CART (0.1, 1.0, and 2.0 g). Food was withheld during physiologic recording and returned for overnight measurement of intake and body weight. CART induced a long-lasting (Ͼ6 h) hypothermia: a 1.5°C and 1.6°C drop in Tc for the 1.0 and 2.0 g doses. Hindbrain CART application reduced food intake and body weight and increased blood glucose levels; no change in HR or activity was observed. Supracollicular decerebration eliminated the hypothermic response observed in intact rats to hindbrain ventricular CART, suggesting that forebrain processing is required for hypothermia. Pretreatment with the GLP-1R antagonist (exendin-9 -39) in control rats attenuated CART hypothermia and hypophagia, indicating that GLP-1R activation contributes to hypothermic and hypophagic effects of hindbrain CART, whereas CART-induced hyperglycemia was not altered by GLP-1R blockade. Data reveal a novel function of CART in temperature regulation and open possibilities for future studies on the clinical potential of the hypothermic effect.

Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6

“…In the present study, in line with earlier studies (42,45,46), we found that EX4 reduced body temperature in the rat. Surprisingly, combined (but not single) blockade of IL-6 and IL-1 partly reversed the hypothermic effect of GLP-1R activation.…”

TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin

“…Therefore, energy expenditure was quantified as the average core temperature and activity beginning 1.5 h after the injection (when activity levels stabilized) until the end of the 6.5-h recording period. As described previously, food was not available during the period of energetic response measurement to avoid diet-induced thermogenesis, which could have confounded the interpretation of the effects of BDNF on energy expenditure (47,49). Food intake and body weight measurements were made immediately before and 24 h after the injection of the drug.…”

“…Rats received a guide cannula (22-gauge; Plastics One, Roanoke, VA) with its tip positioned stereotaxically 2.0 mm above either the 4th ventricle (coordinates: on the midline, 2.5 mm anterior to the occipital suture and 5.2 mm ventral to the skull, with injector aimed 7.2 mm from skull) or the medial NTS at the level of the AP (coordinates: midline Ϯ 0.75, 1.0 mm posterior to the occipital suture and 6.9 mm ventral to the skull, with injector aimed 8.9 mm from skull) (20,21,47,48,51). Cannula were attached to the skull with dental acrylic and jeweler's screws and closed with obturators.…”

Ghrelin directly targets the ventral tegmental area to increase food motivation

“…For the NAcc shell, the following coordinates were used (modified from (Quarta et al, 2009): ±0.75 from the midline, 1.7 mm anterior to bregma, and 6.0 mm ventral to skull, with injector aimed 7.5 mm ventral). Cannulae were attached to the skull with dental acrylic cement and jeweler's screws and closed with an obturator, as described previously (Skibicka et al, 2009). In all rats, the microinjection site for both VTA and NAcc was verified post mortem, by microinjection of India ink at the same microinjection volume (0.5 μl) used throughout the study.…”