The modern Western diet is high in fructose, not from fruits but table sugar and high-fructose corn syrup. Previously in “Can Swapping Fructose for Starch Improve Metabolic Health?”, I discussed how excessive fructose impairs overall metabolic health, which can be reversed by replacing it with glucose or starch like bread or rice. Even in nature, fructose is the primary means by which animals store fat to prepare for food shortages.

That’s the body metabolism on glucose vs fructose. Herein this article would be about the brain on glucose vs fructose.

Brain and Behaviour on Glucose vs Fructose

In 2015, researchers at the University of Southern California gave healthy, non-dieting adults either glucose- or fructose-sweetened beverage. In comparison to glucose, those who drank fructose displayed higher activity in the visual cortex when viewing food images in the fMRI machine. This enhanced visual responsiveness reflects a stronger motivation for food.

At baseline, hormonal levels and appetite ratings were the same. After drinking fructose, participants had a lower rise in plasma insulin than those who drank glucose. “Ingestion of fructose versus glucose also led to greater hunger and desire for food and a greater willingness to give up long-term monetary rewards to obtain immediate high-calorie foods,” the authors wrote.

• In another 2013 brain imaging study, those who drank fructose had lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. This was accompanied by less functional connectivity in the hypothalamic-striatal brain network that regulates satiety and reward. The comparative group was glucose drinkers.
• Similarly, in a 2011 study, healthy adults consuming glucose had higher levels of insulin and activities in cortical brain areas important for behavioural control. The opposite effects were seen in the fructose group, wherein their brain cortex involved in self-control was less activated.
• Again, a 2018 research showed that glucose consumption raised insulin and deactivated the hypothalamus — a brain region commanding food intake — which further correlated with increased satiety ratings. These effects were less apparent with fructose.

These differences in brain and behaviour from glucose vs fructose intake are linked to changes in insulin and glucagon-like peptide levels. What are these two hormones doing to the brain?

The Brain on Insulin

Scientists know since 1989 that consuming fructose stimulates less insulin secretion from the pancreas than glucose. Despite its bad reputation, insulin is a necessary satiety signal for the brain.

In 1981, researchers infused insulin into the brain of baboons and noticed a dose-dependent effect of insulin on appetite suppression. Likewise, infusing glucose into their blood lowered their food intake. The authors postulated that insulin acts as a “body adiposity signal” that tells the brain how much to eat to maintain desirable body fat levels.

Later the “body adiposity signal” was identified as leptin. Leptin-insulin signalling is closely intertwined to regulate energy balance in the body. They act on brain regions that control food intake (e.g., hypothalamus) and dopamine-driven reward behaviour (e.g., ventral tegmental area; substantia nigra, and striatum).

Hence, appropriate amounts of insulin and leptin promote satiation (via hypothalamic signalling) and blunt the rewarding palatability effects of food (via dopamine signalling). Fructose that does not raise insulin as much as glucose would have a less satiation effect.

There’s a catch, however. The above premise only applies to people with normal insulin sensitivity. If the brain is insulin resistant, glucose may not produce higher satiety effects than fructose, which is what’s happening in obese individuals.

The Brain on Glucagon-Like Peptide 1 (GLP-1)

Fructose does not stimulate as much GLP-1 as insulin. GLP-1 plays several vital roles in weight management. It first enhances insulin secretion in response to glucose — enabling higher insulin sensitivity. It slows down gastric emptying, so the stomach stays full longer and then induces glucagon — the hormone that breaks down fats or protein into glucose — secretion.

These roles of GLP-1 make it a suitable target of drugs that promote weight loss in diabetic or obese individuals. Indeed, it is a common practice to infuse GLP-1 into animals to study the effects of appetite and weight loss.

In the brain, GLP-1 is synthesized from the medulla oblongata (a part of the brainstem). In the periphery, GLP-1 is manufactured from intestinal cells, which acts on the vagus nerve that connects to the brainstem. These combined amounts of GLP-1 in the brainstem then influences the brain centre for food intake, hypothalamus, telling the host to stop eating.

The Brain on Ghrelin

Unlike insulin and GLP-1, however, no brain imaging + behavioural studies have yet to see if fructose- or glucose-induced ghrelin responses have any association with brain and behaviour. But theoretically, it should.

Ghrelin — the hunger hormone — levels are decreased to a lesser extent with fructose than with glucose consumption. In people eating the calorically same meals with balanced carbohydrates, fats, and proteins, the meal higher in fructose stimulated less insulin. One to two hours later, ghrelin remained high in the fructose as opposed to the glucose group.

Again, this appears to depend on baseline insulin sensitivity. In a separate study, ghrelin levels in obese people reacted similarly to both fructose and glucose. Whereas in lean people, ghrelin levels reduced after glucose but not fructose intake.

Synthesized from the stomach, ghrelin enters the circulation and crosses the blood-brain-barrier (BBB). Ghrelin then acts on the hypothalamus and dopaminergic pathways, like insulin and GLP-1, but produces opposite effects. It increases hunger (via hypothalamic signalling) and the desire for palatable foods (via dopaminergic signalling).

To sum up

Brain imaging studies have shown that fructose acts on the hypothalamus, cortical areas, and striatal dopaminergic pathways differently than glucose — resulting in increased appetite and reduced satiation.

These behavioural changes are accompanied by the lower rise in circulating insulin and GLP-1 in response to fructose (vs glucose).

Insulin and GLP-1 are signals for the brain to be content with the food consumed. They blunt rewarding effects of more food (via dopaminergic signalling) and the instinctive drive to eat (via hypothalamic signalling). Ghrelin also acts on the same brain areas but yield contrasting effects instead.

Compared to glucose, fructose stimulates less insulin and GLP-1 production. Consequently, fructose would have a lesser (theoretical) effect on ghrelin. A higher intake of fructose would thus be needed to reach the same level of satiation compared to glucose.

Now it makes sense how animals — such as migratory birds and hibernator bears — can consume large amounts of fructose in a short period to prepare fat stores ahead for food shortages. It’s simply easier on the brain to binge on fructose-rich foods than it is with glucose.

Extra: Insulin and BCAAs

Besides glucose, insulin also mediates the uptake of branched-chain amino acids (BCAAs) into muscle cells. BCAAs and tryptophan — the precursor to serotonin — use the same receptor to cross the BBB. So, increased entry of BCAAs into muscle cells enable more tryptophan to enter the brain and be converted to serotonin. And serotonin promotes satiety and “influence food choice by enhancing a focus on long-term goals,” said a 2017 study by UK researchers.

This is also why consuming BCAAs-rich protein shakes can influence brain biochemistry as JJ Lim, BSc (Hons) detailed here: