The Concept of Energy Balance

• Energy intake should be seen as a behaviour which is often influenced by social, environmental, and psychological factors.
• The interaction between peripheral organs and the hypothalamus has an impact on hunger, motivation to eat, satiety, and energy balance.
• The macronutrient composition of the diet also influences energy intake and energy expenditure.
• Obesity and related comorbidities occur when energy intake exceeds energy expenditure over time.
• In sedentary individuals, resting metabolic rate accounts for a large part of total energy expenditure.
• Physical activity increases energy expenditure by increasing resting metabolic rate, enhancing sensitivity to specific hormones, and decreasing post-exercise energy intake.
• Physical activity has the greatest impact on total daily energy expenditure. However, a high level of physical activity is required for this to occur.
• Exercise benefits cardiovascular health and risk factors beyond what can be explained by increased energy expenditure.

The hypothalamus is frequently referred to as the “feeding” or “satiety” centre. The main regions of the hypothalamus involved in energy intake are the arcuate and the paraventricular nucleus. Both regions secrete orexigenic and anorexigenic peptides.

The main role of orexigenic neuropeptides is to restore body fat stores (i.e., restore energy balance) when energy deficits occur. Neuropeptide Y (NPY) is one of the most abundant orexigenic peptides. It is mostly secreted by neurons of the arcuate nucleus and reaches other hypothalamic targets, such as the paraventricular nucleus and the dorsomedial hypothalamic nucleus, prior to feeding [4]. NPY is present at very high concentrations during starvation, but overeating does not raise hypothalamic NPY levels [5]. Similar to NPY, melanin-concentrating hormone (MCH), a peptide produced in the lateral hypothalamus, uses G-coupled receptors to modulate food intake. MCH receptors are found in the hippocampus, amygdala, and cerebral cortex. Though the role of MCH is not fully understood, it has been shown in rats that acute intracerebrovascular injections of MCH can induce intake of high-calorie, energy-dense food, suggesting that it plays a role in energy balance [6]. Ghrelin is an orexigenic peptide produced by the gut, mostly by the cells of the human gastric mucosa. Circulating ghrelin levels are particularly high before feeding and are acutely downregulated by refeeding [7].

Among anorexigenic peptides, leptin plays a crucial role in energy balance. It is mainly secreted by adipose tissue and is a positive correlate of body fat mass in humans [8]. One of the pivotal roles of leptin is to downregulate orexigenic peptides such as NPY and MCH and the signalling lipid 2-arachidonoylglycerol (2-AG) [9]. Leptin receptors are found in the hypothalamus (in the arcuate and paraventricular nuclei and the dorsomedial hypothalamic nucleus), and starvation suppresses leptin levels, which can be reversed by refeeding [10]. Leptin is known to interact with another peripheral anorexigenic peptide, cholescystokinin (CCK), to downregulate short-term food intake [11]. The intestine quickly secretes CCK during the ingestion of a meal, and CCK is involved in reward behaviour, memory, and, especially, satiety [12]. In the periphery, CCK stimulates the endocrine function of the pancreas and encourages intestinal motility.

Within the hypothalamus, there are a number of neuropeptides involved in satiety. The cocaine and amphetamine regulated transcript (CART) is located in the hypothalamus, specifically the paraventricular nucleus, dorsomedial nucleus, and arcuate [3]. Fasting is known to reduce hypothalamic CART mRNA expression, whereas other anorexigenic peptides, such as leptin, raise CART concentrations to encourage satiety [13]. Glucagon-like peptide 1 (GLP-1) acts in the hypothalamic midline nuclei and inhibits desire to eat and food intake. This effect might be due to the inhibition of NPY by GLP-1 or the interaction between GLP-1 and leptin in reducing food intake and body weight, as demonstrated in rats by Goldstone et al. [14].

Among other mediators of neuropeptide release, endocannabinoids have received a great deal of attention with the characterization of the endocannabinoid system and documentation of its role in energy balance. The two major endocannabinoids known to affect energy balance are 2-AG and anandamide. Endocannabinoids bind to and activate cannabinoid-receptor-1 (CB1), which is located in the brain and in the periphery (adipose tissue, liver, GI tract, skeletal muscle, and pancreas). In the brain, CB1 receptors are found in the limbic system, which plays a role in hedonic evaluation of food. They are also found in the hypothalamus and serve to enhance food intake. It has been shown that men with abdominal (especially visceral) obesity have elevated plasma 2-AG levels, suggesting that endocannabinoids may not only be involved in energy balance, but also in regulating body fat distribution and ectopic fat deposition [15,16]. Antagonism of CB1 receptors fosters weight loss, reduces abdominal fat, and improves the cardiometabolic risk profile of men and women with dyslipidemia [17].

The chemical composition of food and its relative macronutrient content play a critical role in regulating food intake and satiety. For instance, unlike carbohydrates and dietary fat, proteins are thought to reduce spontaneous food intake by promoting satiety. The amino acid composition of ingested proteins may also be an important regulator of satiety. Fat and alcohol consumption seems to increase energy intake whereas carbohydrate ingestion does not, although there is evidence to suggest that complex carbohydrates (with a low-glycemic index) may induce satiety similar to proteins [18].

Carbohydrates comprise 45 to 60% of a standard diet and are thought to be the central macronutrient regulating energy balance. Carbohydrates vary widely with respect to chemical composition, absorption, and palatability. Dietary fibres and starches are not absorbed quickly and therefore induce satiety faster than carbohydrates with a high-glycemic index such as sucrose, fructose, and sweeteners. The latter three are absorbed quickly and released in the circulation, thereby playing a critical role in food intake, especially in the intake of high-fat, energy-dense foods [19]. High-fat foods are generally quite palatable, and when humans are allowed to eat high-fat foods without restriction, they often eat more of these foods than when asked to eat low-fat foods under the same conditions in a controlled environment. Because of factors such as palatability and energy density, a high-fat diet may therefore promote a positive energy balance and weight gain [20]. Provided that fat is not replaced by refined sugar, low-fat diets can induce a negative energy balance and are recommended by healthcare professionals to treat overweight and obesity [21,22].

As with carbohydrates, the chemical composition of lipids is another factor that can affect energy intake. It has been shown that substituting medium-chain triglycerides for long-chain triglycerides can promote weight loss in men when energy intake is constant [23]. More importantly, polyunsaturated fats have been shown to decrease the activity of certain lipogenic enzymes and increase fatty acid oxidation in mice [24]. It has also been shown that polyunsaturated fatty acids, unlike saturated fatty acids, promote insulin sensitivity and prevent adipocyte enlargement, which is a marker of fat accumulation [25].

In summary, the factors (both environmental and biological) that influence energy intake are quite heterogeneous and may vary considerably among individuals. In order to stem the obesity epidemic and lessen its growing burden, additional research is needed to better understand and integrate determinants of energy intake, from social and environmental factors to biological and neuroendocrine factors.

Regular physical activity is an excellent way to maintain a healthy body weight and a low-risk metabolic profile. There is a wealth of data proving that physical activity generates cardiovascular and metabolic benefits beyond what can be explained by related energy expenditure.

Regular physical activity can increase resting metabolic rate (RMR), which increases total daily energy expenditure. Sjodin et al. [30] measured the RMR of 8 athletes and compared it to sedentary individuals matched for sex and fat-free mass. They found that for any given amount of fat-free mass, the RMR of athletes was significantly higher than that of sedentary controls. Although the subject is still open to debate, it is generally believed that regular exercise/physical activity can help maintain energy expenditure by having a positive effect on lean body mass (mostly skeletal muscle) [31]. Physical activity also regulates key enzymes involved in energy metabolism. For example, it has been shown that exercise decreases β-adrenoreceptors in the heart while increasing these receptors in skeletal muscle [32,33]. Physical activity also tends to increase post-exercise β-adrenergic stimulation, thereby increasing energy expenditure by boosting lipid oxidation [34]. Moreover, by improving insulin sensitivity, exercise also lowers plasma insulin and glucose levels [35]. Lipoprotein lipase (LPL) is a key enzyme involved in the lipoprotein-lipid metabolism that regulates fat storage in adipose tissue [36]. Exercise reduces LPL activity in adipose tissue but activates LPL activity in skeletal muscle, helping it oxidize more fuel [37]. Exercise also has an impact on LPL response to insulin. For instance, trained athletes are known to have heightened adipose tissue LPL response, which allows them to efficiently replenish adipose tissue lipid stores between exercise bouts [38].

Imbeault et al. [39] quantified the post-exercise energy intake of a group of men submitted to two exercise sessions with the same energy cost. One session was shorter and more intense while the other was longer and less intense. When energy intake relative to expenditure was analyzed by subtracting the surplus of energy expended during exercise from total energy intake, high-intensity exercise led to lower post-exercise energy intake compared to low-intensity exercise sessions. This suggests that high-intensity exercise may lower post-exercise compensation in energy intake.

In summary, the general public should be encouraged to take part in physical activity and exercise whenever possible. Current recommendations include performing at least 30 minutes of moderate-intensity exercise, such as brisk walking, on most days of the week [40]. Regular physical activity can increase daily energy expenditure and create an energy deficit. This deficit can alter energy metabolism and subsequently reduce atherogenic and diabetogenic visceral adipose tissue.