Fructose and Uric Acid as Drivers of a Hyperactive Foraging Response: A Clue to Behavioral Disorders Associated with Impulsivity or Mania?

Abstract

Several behavioral disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and aggressive behaviors are linked with sugar intake and obesity. The reason(s) for this association has been unclear. Here we present a hypothesis supporting a role for fructose, a component of sugar and high fructose corn syrup (HFCS), and uric acid (a fructose metabolite), in increasing the risk for these behavioral disorders. Recent studies have shown that the reason fructose intake is strongly associated with development of metabolic syndrome is that fructose intake activates an evolutionary-based survival pathway that stimulates foraging behavior and the storage of energy as fat. While modest intake may aid animals that would like to store fat as a protective response from food shortage or starvation, we propose that high intake of sugar and HFCS causes a hyperactive foraging response that stimulates craving, impulsivity, risk taking and aggression that increases the risk for ADHD, bipolar disease and aggressive behavior. High glycemic carbohydrates and salty foods may also contribute as they can be converted to fructose in the body. Some studies suggest uric acid produced during fructose metabolism may mediate some of these effects. Chronic stimulation of the pathway could lead to desensitization of hedonic responses and induce depression. In conclusion, a hyperactive foraging response driven by high glycemic carbohydrates and sugars may contribute to affective disorders.

Keywords: Attention Deficit Hyperactivity Disorder; Foraging; Fructose; HFCS; High glycemic carbohydrates; Impulsivity; Starvation; Sucrose.

Figure 1.

Proposed Biological Pathway by which Fructose may have a Role in Behavioral disorders and Obesity and Metabolic Syndrome.

Figure 2. Fructose as a Survival Nutrient that in Excess May Drive Behavioral Disorders.

Figure 2A shows how modest intake of fructose containing foods, such as from fruits and honey, are used by animals to stimulate mechanisms to protect the animal from food shortage. This includes stimulating a foraging response, enhancing fat and glycogen stores, inducing insulin resistances as a mechanism for increasing glucose delivery to the brain, protecting from hypoxia by downregulating mitochondrial function and enhancing glycolysis, increasing sodium levels and maintaining blood pressure, and stimulating innate and adaptive immunity. However, in the setting of excess fructose containing sugars (Figure 2B), these protective mechanisms are overactivated leading to behavioral disorders, along with obesity, diabetes, and other diseases associated with modernity.

Figure 2. Fructose as a Survival Nutrient that in Excess May Drive Behavioral Disorders.

Figure 2A shows how modest intake of fructose containing foods, such as from fruits and honey, are used by animals to stimulate mechanisms to protect the animal from food shortage. This includes stimulating a foraging response, enhancing fat and glycogen stores, inducing insulin resistances as a mechanism for increasing glucose delivery to the brain, protecting from hypoxia by downregulating mitochondrial function and enhancing glycolysis, increasing sodium levels and maintaining blood pressure, and stimulating innate and adaptive immunity. However, in the setting of excess fructose containing sugars (Figure 2B), these protective mechanisms are overactivated leading to behavioral disorders, along with obesity, diabetes, and other diseases associated with modernity.