Paying the Price for Eating Ice Cream: Is Excessive GLP-1 Signaling in the Brain the Culprit?

Abstract

The gut hormone glucagon-like peptide-1 (GLP-1) is an important regulator of glucose homeostasis and energy balance through its concerted actions on appetite, islet hormone secretion, glucose clearance, and gut motility (1) and is a leading candidate for treatment of type-2 diabetes and obesity. The secretion of GLP-1 from L-cells in the distal gut is stimulated by local luminal nutrients (2), and perhaps by a neural reflex involving nutrient sensors in the proximal gut (3). It is thought that G protein-coupled long-chain fatty-acid receptors, including GPR119 on L-cells in the distal gut are responsible for fat-stimulated GLP-1 release (4). However, GLP-1-secreting L-cells have recently also been described in the human and rodent duodenum, where glucose and artificial sweeteners are able to stimulate release of GLP-1 via the same sweet taste receptor mechanisms found in oral taste buds (5). Not only is the gut copying nutrient sensing mechanisms from the taste bud, but cells in the taste bud are also producing GLP-1 that can activate taste nerves bearing GLP-1 receptors (6,7) (see Fig. 1​1). Figure 1 GLP-1 is produced and released from enteroendocrine L-cells in the small intestine, taste receptor cells, and neurons in the brainstem. Peripheral GLP-1 is signaling via vagal and taste afferents to the nucleus of the solitary (NTS) tract in the brainstem ... Once released, GLP-1 is rapidly cleaved by the ubiquitous serine protease dipeptidyl-peptidase IV (DPP-IV), so that the half-life of circulating GLP-1 is only a few minutes. However, there are two mechanisms that protect GLP-1’s potency for remote signaling. First, sensory vagal nerve fibers innervating the gut mucosa and expressing GLP-1 receptors (8) are in close anatomical contact to the base of enteroendocrine cells (9). Second, GLP-1 entering intestinal lymph appears to be protected from rapid degradation and available for delayed release to the circulation (10). Furthermore, GLP-1 is produced by a small group of neurons in the nucleus tractus solitarius (NTS) in the caudal brainstem and released as a neuromodulator within the brainstem and hypothalamus (11). Because these neuronal GLP-1 projections receive input from the gut via vagal afferents (12), likely including GLP-1 sensitive afferents from the intestinal mucosa and the hepato-portal vein (13), they might be considered as an additional mechanism for amplification of the rapidly fading peripheral GLP-1 signal. Although GLP-1 can act directly in the periphery via GLP-1 receptors in various tissues, more and more of its effects are now being demonstrated to have a central nervous relay. Obviously modulation of appetite has an obligatory neural component, and administration of GLP-1 or its stable agonist Exendin-4 directly into the brain potently decreases, whereas the GLP-1 receptor antagonist Exendin-9 (Ex9) increases food intake (14,15). However, to what extent GLP-1 signaling within the brain is also involved in the regulation of glucose homeostasis has not been clear. This question is addressed by Knauf and colleagues in an article in this issue of Endocrinology (16). They earlier reported that, in the postabsorptive state, brain infusion of the GLP-1 receptor agonist Exendin-4 enhanced insulin secretion, reduced insulin-stimulated muscle glucose utilization, and increased liver glycogen storage, whereas brain GLP-1 receptor antagonism produced the reverse effects (17). They thus hypothesized that overabundance of food in the gut may lead to exaggerated activation of the gut-brain axis and central GLP-1 signaling, resulting in decreased muscle glucose utilization and ultimately insulin resistance. They found that chronic blockade of central GLP-1 signaling by lateral ventricular infusion of Ex9 almost completely prevented hyperinsulinemia and insulin resistance in mice fed a high-fat diet for 30 d (16). Both, fasting hyperglycemia and hyperinsulinemia, as well as ip glucose tolerance, were almost completely normalized by brain blockade of GLP-1 receptor signaling. In stark contrast and reported earlier, blockade of peripheral GLP-1 signaling induced fasting hyperglycemia and glucose intolerance. High-fat diet-induced insulin resistance, as indicated by decreased whole body glucose utilization and hepatic glycogen synthesis, was normalized by brain Ex9 infusion. Most intriguingly, despite robust hyperphagia, body weight remained unchanged in high-fat fed mice infused in the brain with Ex9 compared with vehicle. This seemingly paradoxical outcome was possible because postabsorptive energy expenditure was dramatically increased with brain GLP-1 blockade, as indicated by increased insulin-sensitive glucose utilization in glycolytic muscle and white adipose tissue, as well as increased locomotor activity and cold-induced thermogenesis (16). These effects are convincing because they were achieved with blockade of endogenous brain GLP-1 signaling rather than the use of high, nonphysiological doses of receptor agonist. The results suggest that the development of high-fat diet induced insulin resistance depends on hyperactive brain GLP-1 signaling and has potentially far reaching implications for the treatment of type-2 diabetes. In a companion paper, Knauf et al. (18) showed that selective activation of gut glucose sensors increased muscle glycogen synthesis via a central relay requiring intact GLP-1 signaling and that this mechanism is impaired by diabetes. Thus, just when it appeared that GLP-1 is a premier guardian of healthy glucose homeostasis, the observations by Knauf et al. (16) uncover a potential dark side of excessive central GLP-1 signaling. However, food is never eaten as hot as it is cooked, and there are a number of caveats in the approach used by Knauf et al. that could explain the findings in different ways. First, the high-fat diet used was completely carbohydrate free. Although the reason for this special diet was to reveal diet-induced diabetes before the development of confounding obesity, the drastic effects observed may be unique to this exotic diet, with little implications for a food environment characterized by high sugar and fat such as in ice cream. At face value, it seems difficult to reconcile the use of a carbohydrate-free diet with a key regulator of glucose homeostasis, and only future studies with other diet compositions will show whether the sweeping conclusions hold up. Second, GLP-1 signaling in the brain is likely to be anatomically and functionally discrete but was blocked indiscriminately throughout the brain in the Knauf et al. study (16). Although not ubiquitous, the GLP-1 receptor is expressed in a number of brainstem, midbrain, and forebrain areas, particularly in several nuclei of the hypothalamus that have different functional connotations (19,20). Given the contrasting effects of peripheral and central GLP-1 signaling highlighted in the Knauf et al. study (16), it seems likely that this dichotomy extends to the brain. This interpretation is supported by the observations that GLP-1 injected locally into the arcuate nucleus reduces hepatic glucose production but does not affect food intake (20), whereas injection into the paraventricular nucleus of the hypothalamus suppresses food intake. Furthermore, selective activation of GLP-1 receptors in the caudal brainstem was sufficient to suppress food intake, gastric emptying, and core body temperature in rats (15), likely involving GLP-1 receptors on area postrema neurons projecting to both vagal and sympathetic output systems (21). A related issue is the source of ligand for a given effect. It will be important to determine which brain GLP-1 receptors are activated by GLP-1 originating in gut enteroendocrine cells, and which by GLP-1 originating from brainstem neurons. Circulating GLP-1, although rapidly degraded by DPP-IV, can freely cross the blood-brain barrier (22). Involvement of the brain GLP-1 system in the effects observed by Knauf et al. (16) is indicated by significantly increased proglucagon gene expression in the caudal brainstem. However, this finding does not rule out stimulation of specific brain targets by separate or combined actions of both circulating and neuronally released GLP-1. It also needs to be determined whether Ex9 penetrates the blood brain barrier as freely as GLP-1. Thus, whereas inhibition of brain GLP-1 signaling appears to protect from high-fat diet-induced diabetes (16), stimulation of the same receptor has strong neuroprotective effects (23). How is it possible that completely opposite manipulations of the same signaling system can both be beneficial? Only further defining the central neural circuitry and molecular mechanisms involved in each of these effects will provide answers to this question.