Growth factor study reveals potential breakthrough in obesity management

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMJul 4 2023

An 'obesity epidemic' is affecting the world. Medical, surgical, exercise-related, and dietary measures are all being marketed worldwide to prevent or reduce this condition.

A new paper in Nature discusses the effects of a growth factor that showed promising results in mice in an obesity trial.

Study: GDF15 promotes weight loss by enhancing energy expenditure in muscle. Image Credit: 279photoStudio/Shutterstock.com

Introduction

Dietary restriction is often recommended in weight loss programs. It aims to reduce the calories available to the body, thus promoting the catabolism of stored lipids from fat storage depots, especially visceral fat.

It also improves the sensitivity of the peripheral tissues, especially skeletal muscle, to the hormone insulin that promotes glucose uptake and utilization, thus reducing the glucose levels in the blood.

However, weight loss is easier to achieve than maintain in most individuals. This is partly because intense dietary restrictions lead to cravings that overcome the motivation to keep off certain palatable foods.

In the current study, scientists fed rodents with fatty food and the recombinant growth differentiating factor 15 (GDF15). This protein is found in the kidneys and liver tissues at high levels. However, it may be synthesized in all types of cells under certain stress conditions.  

GDF15 was first found to be produced from cancer cells and macrophages and causes profound weight loss. It prevented the development of obesity and insulin resistance in mice, even when fed on a high-fat diet.

GDF15 led to weight loss in such rodents and reduced non-alcoholic fatty liver disease (NAFLD) while normalizing blood glucose levels.

In the hindbrain, these effects are mediated by the glial-cell-derived neurotrophic factor family receptor α-like (GFRAL) pathway.

Prior research shows that in about ten days, GDF15 causes reduced food intake in mice, leading to weight loss. This would appear to offer that the primary effect of this factor on weight loss is via appetite suppression.

However, energy intake, expenditure, and body weight are interlinked. Thus, weight loss or reduced energy intake typically reduces energy expenditure. This response, termed adaptive thermogenesis, is a counter-regulatory mechanism to increase the odds of survival when faced with food shortages.

The short period of most rodent studies precludes the ability to pick up such changes, which occur after caloric restriction of a longer duration. Again, mice kept at room temperature, that is, at 21 °C, are below their preferred temperature (29 °C), driving sympathetic responses. This could prevent weight loss from occurring in response to β-adrenergic-dependent agents.

This led to the current study exploring how these interrelated factors impact weight loss following GDF15 use in mouse models.

What did the study show?

In this experiment, mice were kept at their thermoneutral temperature of 29 °C and given a high-fat diet rich in fructose. This led to high weight, insulin resistance, and non-alcoholic steatohepatitis (NASH) changes.

At tissue and transcriptional levels, the changes reflected those in humans on a typical Western diet.

Mice were treated with GDF15 at the beginning of the light and dark cycles. Mice eat most during the dark cycle. In the former case, their food intake was reduced by a third, but by almost half in the latter, consonant with the difference in food intake under normal conditions in these two phases.

Having proved this, the researchers then divided the next group of mice into three dosage groups, at 0.3, 1, and 5 nmol per kg of GDF15, injected at the start of the light cycle, for six weeks, with a control group for comparison.

All groups were given a high-fat diet, and the actual amount consumed by each mouse was measured and matched between the treatment group and control mice.

This long phase of GDF15 treatment led to the expected reduction in food intake in a dose-dependent manner. No significant effect was found in mice treated with the lowest dosage.

In the other two treatment groups, treated and control pair-fed mice showed the same weight loss trends for the first ten days. Following this period, body mass loss evened out in pair-fed mice.

In contrast, when GDF15 was given for over ten days, sustained weight loss occurred, exceeding that associated with caloric restriction alone. By the end of the experiment, the treatment groups (1 and 5 nmol/kg) lost about 14% and 23% of their body mass, respectively, vs. 5% for the control pair-fed mice.

Most of this loss was due to fat mass loss. Serum insulin levels also decreased, as expected from the lowering of body and fat mass. Mice at the highest dosage level showed better glycemic control and insulin sensitivity than controls.

These data indicate that GDF15 in a chronic setting promotes reductions in body mass and reduces insulin resistance to a greater degree than caloric restriction alone."

The results also showed that the rodents ate less, but still used up energy as usual, thus promoting weight loss. This occurred irrespective of housing temperature, but more energy was expended at the lower temperature.  

The weight loss was still higher when a higher dose of GDF15 (8 nmol/kg) was used, irrespective of whether the mice were fed at the start of the light or dark cycles. This was observed in two different pair-fed groups of mice at another research site.

NASH improved in GDF15-treated mice compared to controls exposed only to caloric restriction, showing the independent effect of GDF15.

GDF15 acts not only by suppressing energy intake but also by sustaining energy expenditure during times of caloric restriction. It does so by a pathway involving the GFRAL receptors, found only in the hindbrain.

GFRAL activity was not observed to impact fatty acid oxidation via β-adrenergic signaling within fatty tissue. Its preferred target appears to be skeletal muscle.

This occurs via β-adrenergic receptors that produce signals enhancing fatty acid oxidation and increasing futile calcium cycles within the skeletal muscle fibers in mice.

Calcium futile cycles uncouple calcium metabolism in the muscle cell from contraction. These enhance skeletal muscle energy expenditure, explaining the effect of GDF15 on weight loss.

Calcium cycling accounts for half the energy spent in skeletal muscle or about 15% of the body's energy. An increase in GDF15-related futile calcium cycling would thus increase total energy expenditure by about 5%, or about 100 kcal.

Epidemiological investigations using two-sample Mendelian randomization (2SMR), using genome-wide association study (GWAS) summary-level data to compare the liver fat content and volume on participants in the UK Biobank study, confirmed the benefit of GDF15 in reducing liver fat content without shrinking liver volume.

These data indicate that GDF15 is associated with reduced NAFLD in clinical populations."

What are the implications?

The effect of GDF15, when administered for a long period, favors weight loss and insulin sensitivity, with reduced NAFLD activity, to a larger extent compared to caloric restriction alone.

These data indicate that therapeutic targeting of the GDF15–GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction."

The effect of GDF15 is thus equivalent to that of modest caloric restriction.

During weight loss experiments, further research is required to explore the associations between GDF15, futile calcium cycling in skeletal muscle, and energy expenditure in human physiology.