It is well established that systemic administration of exogenous GLP-1(7-36) or GLP-1R analogues (e.g. Liraglutide, Exanatide) reduces food intake in a dose-dependent manner in rodents, non-human primates and humans [11
]. This intake inhibitory effect of peripheral pharmacological GLP-1R activation is sustained in obese humans even in the presence of T2DM [43
], and has therefore prompted research evaluating the efficacy of DPP-IV-resistant GLP-1R ligands as candidates for obesity treatment. Indeed, systemic administration of either Liraglutide or Exanatide has been shown to reduce body weight in both animal models and humans (see for review [22
]). Interestingly, it appears that pharmacological activation of systemic GLP-1Rs (2x daily administration of Byetta [Exanatide]) produces the greatest magnitude of weight loss in the most morbidly obese individuals compared to weight loss observed in overweight or lean humans [31
]. While the significant reduction in body weight for these obese patients following ~2 years of Byetta treatment was approximately 11 lbs, the slope of weight loss was sustained over the treatment period [31
]. It is possible that chronic GLP-1R activation following systemic DPP-IV resistant GLP-1R treatments continues to produce intake inhibitory- and body weight suppressive-responses with a lack of “resistance” (e.g., diminution of response when ligand levels are chronically elevated). These findings highlight the need for further evaluation of the GLP-1 systems in treating not only T2DM but also obesity through the careful design of more effective pharmacological treatments that chronically target the peripheral (and perhaps central) GLP-1 system.
The strength of the peripheral GLP-1 system as a candidate for obesity treatment is highlighted by research employing GLP-1 antagonist treatment to assess the endogenous role of this system in intake control. Recent evidence by Williams et al. [30
] suggest that endogenous peripherally secreted GLP-1 plays a physiological role in food intake suppression by showing that intraperitoneal (IP) administration of the GLP-1R antagonist, Exendin-9 (9-39), attenuates the intake suppressive effects that follow voluntary consumption and intragastric infusion of a liquid meal in rats. Further, a recent report by Reimer et al. [46
] showed that mice treated with the DPP-IV inhibitor NVP DPP728 in the drinking water decreased weekly food intake when maintained on either standard rodent chow or high fat diet.
While the effects of peripheral GLP-1 agonist and antagonist treatment support a strong role for this system in the inhibitory controls of intake and body weight regulation, models of GLP-1R deficiency in mice have not been consistent with this interpretation. For instance, the GLP-1R knockout mouse is surprisingly lean, exhibits unaltered meal patterns, and does not develop obesity with aging or after several months of high fat diet maintenance [47
]. These findings, which seem to be very different from the profile of responses observed in humans, non-human primates, and rats, have certainly raised many questions regarding the role of GLP-1R signaling in food intake and body weight regulation [11
]. In fact, clear species differences have also been reported between mice and rats for GLP-1R-mediated control of visceral illness; in particular in LiCl-induced anorexia [49
]. Likewise, species differences between the mouse and rat have also been reported with regard to the regulation of central GLP-1-immunoreactive neurons in the NTS by the adiposity hormone leptin [50
]. It was reported that leptin induced phosphorylation of signal transducer and activator of transcription-3 (pSTAT3) in 100% of GLP-1 cells in the caudal brainstem of mice, whereas in rats a complete absence of pSTAT3 was observed in NTS GLP-1-positive neurons following leptin treatment [50
]. Moreover, this same report showed that in mice, proglucagon mRNA was reduced by food deprivation, and this was prevented by leptin administration; whereas proglucagon mRNA was unaffected by either fasting or leptin treatment in rats [50
]. The take home message here is two-fold: 1) caution should be taken when making generalizations between the mouse and rat regarding the role of peripheral GLP-1 in energy regulation, and 2) the question of which species (rat or mouse) represents the appropriate model to understand the normal physiology and pathophysiology of human diseases is not straight forward, and will always depend on the physiological system under investigation.
The aforementioned report by Williams et al. [30
] directly addressed the ongoing debate of whether administration of systemic GLP-1R ligands produce their intake inhibitory response through activation of peripheral or central GLP-1Rs. They reported that central blockade of GLP-1R attenuated only the intake suppression by central GLP-1 administration, whereas the intake suppression following peripheral (IP) GLP-1 administration was only attenuated following peripheral administration of the GLP-1R antagonist Exendin-(9-39) [30
]. These findings support the notion that while the direction and profile of responses are similar for peripheral and central application of GLP-1R agonists, the two populations of receptors may in fact be considered the mediators of separate (peripheral vs. central) GLP-1 systems. Further support for this perspective comes from a wide variety of studies detailed below.
A number of findings support a role for vagal afferent fibers in mediating the intake suppressive and glycemic responses to exogenous systemic GLP-1R ligand administration. For instance, elimination of vagal afferent signaling via surgical or chemical deafferentation of the vagus attenuates GLP-1R-mediated suppression of food intake and gastric emptying, and inhibits GLP-1R-mediated increases in gastric acid secretion and glucose-induced insulin secretion (see [22
] for review). CNS processing of GLP-1R-mediated vagal afferent
activation has been shown to stimulate pancreatic-projecting vagal efferents
that enhance insulin secretion [51
]. Thus far, systemic GLP-1R-mediated control of glycemia has been attributed to either GLP-1R-expressing vagal afferent nerve terminals in the hepatic portal bed [14
], or to direct activation of GLP-1R expressed on pancreatic β-cells (see for review [22
]). This conclusion rests on the observation that intraportal infusion of a GLP-1R antagonist produced a hyperglycemic response following intragastric glucose infusion in anesthetized rodents, whereas, delivery of the same dose of the GLP-1R antagonist to the jugular vein did not alter the plasma glucose or insulin response following intragastric glucose infusion. However, a focused examination of the physiological role of GLP-1R signaling on GI-innervating vagal afferent fibers in glycemic control is needed. This notion is supported by findings from Rüttimann et al. [53
] showing that the satiating effect of IP, but not intravenously (intrajugular or intrahepatoportal) administered GLP-1, requires vagal afferent signaling. Thus, an IP route of administration may represent a more physiological profile of action for the GLP-1R, taking advantage of the putative paracrine-like profile of endogenous GLP-1R activation in the small intestine. It is interesting to consider that general intravenous administration of GLP-1 (femoral vein infusion) can increase vagal afferent mass activity [54
], and yet this electrophysiological response does not appear to be required for the suppression in meal size by IV infusion of GLP-1, while vagal activation is required for response production by IP GLP-1 [20
]. The speculative conclusion of this discrepancy is a cautionary comment: That neuronal excitability of the vagus in an anesthetized preparation does not always equate to a CNS-dependent behavioral response (e.g. suppression of ongoing food intake).
The finding of Rüttimann et al. [53
] suggest that GLP-1R expressed on vagal afferents innervating the hepatoportal region may not be required for mediating the intake suppressive effects of GLP-1. Instead, the finding that intraportal infusion of a GLP-1R antagonist produces a hyperglycemic response following intragastric glucose infusion [34
] suggests that for vagal afferent GLP-1R populations in the periphery, the control of glycemic responses may be dissociable from the food intake inhibitory responses. Equally likely, however, is that endogenous GLP-1 signaling acting in a paracrine fashion on adjacent GLP-1Rs expressed on vagal afferents innervating the GI tract controls both intake and glycemia, while GLP-1Rs expressed on hepatoportal vagal afferents only control glycemic responses. Future analysis is certainly needed to determine which populations of peripheral GLP-1Rs are required for the intake suppressive- and incretin-mediated effects by systemic GLP-1.
An additional interesting piece of evidence with regard to GLP-1’s site-of-action comes from the finding that the meal size suppressive effects produced by jugular GLP-1R ligand administration do not require vagal afferent mediation [53
]. This suggests that GLP-1R expressed on splenic fibers may be mediating this response, or that GLP-1 infusion in the jugular vein, at levels above what would normally be seen under endogenous circumstances [22
], are producing their intake-inhibitory response through direct activation of GLP-1Rs-expressed in the brain, likely at nuclei classified as or adjacent to circumventricular organs (CVO). The extremely short half life (1-2 minutes) and minimum penetration through the blood brain barrier by GLP-1 makes direct action in the CNS negligible under endogenous circumstances [22
]. Clearly the brain CVO, e.g. AP and subfornical organ (SFO), plays a role in responses generated by peripheral endocrine hormones acting in the CNS [55
]. However, a very recent report shows that ablation of both the AP and the SFO does not attenuate the intake inhibitory effects that follow IP administration of the GLP-1R agonist, Exendin-4 [56
]. Thus, splenic mediation seems to be the more likely mediator of the intake inhibitory response to GLP-1R ligands present in general circulation (i.e. jugular vein), particularly when considering recent findings that suggest a dissociation between the mechanism through which peripheral vs. central GLP-1R activation produces an intake inhibitory response.
It is generally well accepted that peripheral GLP-1 ligand administration (IP, IV, or subcutaneous) reduces food intake through a reduction in meal size [20
], and has even been recently categorized as a satiation signal [30
]. However, a recent preliminary report shows that hindbrain activation of brain GLP-1Rs reduces food intake by reducing meal number (thus increasing the inter-meal-interval), not through an alteration in meal size [57
]. This finding further highlights the strength of the GLP-1 systems as potential candidates for obesity treatment, as future treatments designed to target both peripheral and central GLP-1 systems would potentially offer an avenue to decrease not only the size of the meals being consumed, but potentially the number of meals and/or snacks taken in a day.