A series of experiments in mice demonstrates that a well-known hormone might have a previously unidentified role in the metabolic response to energy restriction during weight loss.

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A recent study finds a new role for an old hormone.

Scientists have known about growth hormone (GH) for several decades. It plays a role in bone growth and is particularly important as our bodies grow.

It also helps maintain organs and tissues as we go through our adult lives.

However, researchers at the University of São Paulo in Brazil have found an entirely new and unexpected role for GH: It appears to play a part in energy conservation during weight loss.

José Donato Junior and his team published their findings in the journal Nature Communications.

When an animal's food intake becomes restricted, its body responds by conserving energy.

This mechanism is important because, in the wild, if an animal is having difficulty finding food, the body needs to save as much energy as possible.

However, this is part of the reason why it is incredibly difficult to prevent weight from returning after dieting. For many years, researchers have tried to zero in on why this might be the case.

Hormones and weight loss

Scientists already know that a hormone called leptin plays a part in the body's response to weight loss. Fat cells produce leptin, which inhibits hunger. When we lose weight, levels of leptin in the bloodstream drop, making us more likely to feel hungry.

Some people can develop leptin resistance, which means that they no longer respond to the hormone and, consequently, feel hungry more often.

As Donato explains, "Leptin has hitherto been considered the main hormone that acts to conserve energy when we're hungry."

However, despite scientists' growing understanding of leptin, it has not led to any successful weight-loss interventions. The most recent study asks whether GH might be one of the missing pieces of the puzzle.

"GH receptors are found in large quantities in muscle and tissue, in the liver, and in organs directly involved in growth metabolism," says Donato, "but we found that the brain is also full of GH receptors. This is entirely new."

The scientists demonstrated that leptin levels decrease in response to a restriction in caloric intake, while levels of GH increase.

Where are the GH receptors?

The scientists found an abundance of GH receptors in the hypothalamus. The hypothalamus regulates the autonomic nervous system, which is the arm of the nervous system that controls automatic functions, such as breathing and digestion.

The hypothalamus also plays an important role in controlling energy homeostasis — the regulation of energy expenditure and food intake.

In the hypothalamus, a small collection of neurons produce agouti-related protein (AgRP). When these neurons release AgRP into the body, appetite increases, and the body holds onto its energy stores more tightly.

The scientists found that GH receptors in the hypothalamus activate these neurons, triggering the release of AgRP.

To understand what influence GH might be having on AgRP neurons, the researchers genetically engineered a strain of mice that lacked the AgRP-specific GH receptor (AgRP GHR KO mice).

In a series of experiments, the scientists deprived mice of food and assessed their energy expenditure.

The control mice, which still had the GH receptor, responded to restricted food intake as expected by reducing their energy expenditure.

However, in the AgRP GHR KO mice, the drop in energy expenditure was much less pronounced. Consequently, these mice lost more weight over the course of the study. The loss of energy-dense fatty tissue accounted for most of this weight decrease, but there was also some loss of lean mass, which includes muscle, bone, organs, tendons, and fluids.

Blocking growth hormone

In a separate experiment, the researchers used mice that they had not engineered to lack the GH receptor. This time, they used a drug called pegvisomant that blocks GH receptors instead.

Once again, with food deprivation, the energy expenditure of these mice decreased significantly less than it did in mice that had not received pegvisomant.

"GH is not only involved in growth metabolism but, above all, influences the metabolic responses that conserve energy when we're hungry or on a diet," concludes Donato.

"In other words, we discovered that weight loss triggers an increase in hypothalamus GH levels, which activates the AgRP neurons, making weight loss harder and intensifying the sense of hunger. That's precisely the same function leptin performs."

Lead author José Donato Junior

The authors conclude that GH does not appear to play a significant role in energy balance when the animals have adequate access to food. Instead, it "signals energy deficiency to the brain, triggering neuroendocrine responses to conserve body energy stores."

Donato explains that because conserving energy is so important for survival, animals appear to have evolved two separate systems.

The authors also hypothesize that this might be why weight-loss interventions based solely on leptin are ineffective — they are only addressing part of the mechanism.

In the future, the authors believe that compounds that target GH receptors could "represent a promising approach to facilitate weight loss and improve the efficacy of obesity treatments."