Dietary sugars and non-caloric sweeteners elicit different homeostatic and hedonic responses in the brain

Highlights

• Glucose elicits an immediate deactivation of the hypothalamus.

• Sucrose and fructose elicit a delayed deactivation of the hypothalamus

• The non-caloric sweetener sucralose elicits a transient hypothalamic response

• In the ventral tegmental area, sucralose elicits a very similar activation to plain water ingestion

• The natural sugars appeared to only elicit a transient, if any, increase in ventral tegmental area activity

Abstract

Objective

The brain is essential in regulating intake of food and beverages by balancing energy homeostasis, which is regulated by the hypothalamus, with reward perception, which is regulated by the ventral tegmental area (VTA). The aim of this study was to investigate the effects of ingestion of glucose, fructose, sucrose, and sucralose (a non-caloric artificial sweetener) on the magnitude and trajectory of the hypothalamic and the VTA blood oxygen level–dependent (BOLD) responses.

Method

In five visits, 16 healthy men between 18 to 25 y of age with a body mass index between 20 and 23 kg/m² drank five interventions in a randomized order while a functional magnetic resonance imaging scan was taken. The interventions consisted of 50 g of glucose, fructose, or sucrose, or 0.33 g of sucralose dissolved in 300 mL tap water. The control condition consisted of 300 mL of plain tap water. BOLD signals were determined in the hypothalamus and the VTA within a manually drawn region of interest. Differences in changes in BOLD signal between stimuli were analyzed using mixed models.

Results

Compared with the control condition, a decrease in BOLD signal in the hypothalamus was found after ingestion of glucose (P = 0.0003), and a lesser but delayed BOLD response was found after ingestion of sucrose (P = 0.006) and fructose (P = 0.003). Sucralose led to a smaller and transient response from the hypothalamus (P = 0.026). In the VTA, sucralose led to a very similar response to the water control condition, leading to an increase in VTA BOLD activity that continued over the measured time period. The natural sugars appeared to only lead to a transient increase in VTA activity.

Conclusions

Glucose induces a deactivation in the hypothalamus immediately after ingestion and continued over the next 12 min, which is correlated with satiety signaling by the brain. Fructose and sucrose are both associated with a delayed and lesser response from the hypothalamus, likely because the sugars first have to be metabolized by the body. Sucralose leads to the smallest and most transient decrease in BOLD in the hypothalamus and leads to a similar response as plain water in the VTA, which indicates that sucralose might not have a similar satiating effect on the brain as the natural sugars.

Introduction

The human brain is essential in regulating the intake of food and beverages by balancing energy homeostasis with reward perception [1]. The hypothalamus is an important structure that regulates energy homeostasis by integrating information from glucose and insulin trajectories with varying levels of hormones and peptides from the gut and stomach [2], [3], [4], [5]. The mesolimbic pathway, in conjunction with homeostatic regulation, is responsible for the hedonic response to food. The ventral tegmental area (VTA) and other areas of the limbic system (amygdala, nucleus accumbens) are important parts of the mesolimbic pathway involved in this hedonic response [6]. The VTA is the origin of dopaminergic neurons and dopamine signaling in the mesolimbic system, which is a key substrate for reward prediction and response [7]. The VTA is anatomically and functionally connected to the hypothalamus and integrates homeostatic signals with reward responses [8], [9], [10]. Both homeostatic and mesolimbic pathways respond to glucose, which is the natural and preferred source of energy for the body and brain [11], [12]. Glucose concentration in the blood is kept under tight homeostatic control, partly mediated by glucose-sensing neurons in the brain [12]. Glucose intake leads to changes in hypothalamic blood oxygen level–dependent (BOLD) levels, which have been interpreted as a sign of satiety [4], [13]. However, little VTA data are available [14], and further investigation into the VTA may be essential in the understanding of the integration of homeostatic and hedonic responses regulation feeding behavior [6].

In many foods and beverages, monosaccharides and disaccharides or artificial sweeteners are used as sweeteners [15]. It has been suggested that increased consumption of these sugars and sweeteners in the modern diet plays a role in pathophysiology of obesity, decreased vascular health, metabolic syndrome, and type 2 diabetes [15], [16], [17], [18]. High fructose consumption also has been hypothesized to have detrimental health effects, is associated with fatty liver disease, and has been shown to have greater adverse effects on metabolism and vascular health than glucose in several animal studies [19], [20]. Fructose is used as a sweeter alternative to glucose, allowing for the use of smaller amounts, but the metabolism of both sugars is very different. In contrast to glucose, fructose cannot be used directly as a source of energy [21]. Fructose, which is a naturally occurring saccharide in fruits and vegetables, has to be metabolized by the liver before it can be made available as a source of energy [22]. Fructose can be consumed in its free form as a monosaccharide in fruits and high-fructose corn syrup but also in the form of sucrose, which is a glucose–fructose disaccharide. In addition to the use of added natural sugars, non-caloric artificial sweeteners are increasingly being used to sweeten foods and beverages. The use of non-caloric sweeteners could be expected to decrease total caloric intake and might therefore be useful to control obesity [23]. However, some epidemiologic studies suggest that non-caloric sweeteners might have the opposite effect and might actually lead to increased energy intake [5], [24], [25]. Although these results are not conclusive and the effects of non-caloric sweeteners remain a subject of debate, these results do indicate that these sweeteners could have unexpected effects in the brain. Currently, the homeostatic and mesolimbic effects in the brain of these sweeteners and other common dietary sugars are unknown. The differences in how various sugars are metabolized and made available as energy, and because of the decoupling of sweetness and energy in non-caloric sweeteners, each could lead to different metabolic and physiological responses in the brain [26], [27], [28], [29].

To gain a better understanding of the different homeostatic and hedonic responses after ingestion of caloric and non-caloric sweeteners, we investigated the effects of glucose, fructose, sucrose, and sucralose (an artificial non-caloric sweetener) on the trajectory and magnitude of BOLD response of the hypothalamus and VTA in young men of normal weight.