Neuroendocrine and Metabolic Effects of Low-Calorie and Non-Calorie Sweeteners

Abstract

Since excessive sugar consumption has been related to the development of chronic metabolic diseases prevalent in the western world, the use of sweeteners has gradually increased worldwide over the last few years. Although low- and non-calorie sweeteners may represent a valuable tool to reduce calorie intake and prevent weight gain, studies investigating the safety and efficacy of these compounds in the short- and long-term period are scarce and controversial. Therefore, future studies will need to elucidate the potential beneficial and/or detrimental effects of different types of sweeteners on metabolic health (energy balance, appetite, body weight, cardiometabolic risk factors) in healthy subjects and patients with diabetes, obesity and metabolic syndrome. In this regard, the impact of different sweeteners on central nervous system, gut hormones and gut microbiota is important, given the strong implications that changes in such systems may have for human health. The aim of this narrative review is to summarize the current evidence for the neuroendocrine and metabolic effects of sweeteners, as well as their impact on gut microbiota. Finally, we briefly discuss the advantages of the use of sweeteners in the context of very-low calorie ketogenic diets.

Keywords: VLCKD; body weight; diabetes; metabolic health; microbiota; obesity; safety; sugar.

Figure 1

Brain reward circuitry involved in central effects of sweeteners. The dopaminergic pathway is strictly involved in hedonic processes (“liking”), reinforcement (“learning”), and motivation (“wanting”). Midbrain dopaminergic circuits include Lateral Hypothalamus (LHA), Ventral Tegmental Area (VTA), and Nucleus Accumbens (NAc). Dopamine release is driven by orexin (ORX) peptides and melanin-concentrating hormone (MCH) secreted by LHA. In particular, ORX and MCH neurons from LHA project to VTA, where Orx peptides and MCH mediate the activation of dopamine (DA) neurons and increase the release of DA in projection areas such as the NAc. It has been established that dopamine reward pathway response induced by caloric sweeteners consumption, such as sucrose, is greater compared to non-calorie sweetener sucralose. Interestingly, a preclinical study provided evidence that MCH neurons account for the natural preference for sucrose over sucralose and that such effect can be reversed by stimulating MCH neurons with light. This suggests that non calorie-sweeteners require additional stimuli to obtain the same rewarding effect of sucrose.

Figure 2

Effects of non-calorie sweeteners in the gastrointestinal tract. Non-caloric sweeteners bind to sweet-taste receptors (T1Rs) on enteroendocrine L-cells, promoting the synthesis of a series of second messengers, which ultimately results in GLP-1 release. GLP-1 stimulates the peripheral endings of afferent nerve fibers—which send GLP-1-signal toward the central nervous system—and promote neuropeptide release by enteric neurons, thus triggering the up-regulation of SGLT1 in enterocytes. Therefore, GLP-1 signaling ultimately results in increased intestinal glucose absorption. On the other hand, the role of circulating GLP-1 in eliciting glucose-dependent insulin secretion by pancreatic β-cells is well-established. These molecular mechanisms have been demonstrated both in vitro and in vivo, in preclinical studies, although they still need to be confirmed in clinical studies. GLP-1, glucagon-like peptide 1; SGLT1, sodium-dependent glucose cotransporter-1.