We’ve all seen the headlines – Ozempic portrayed as the Hollywood drug, the instant solution to weight loss for those in the public eye. But it also comes with side effects and the regaining of some of the weight once the treatment stops. So where are we in this field that has advanced rapidly in recent years, and what is the future?
“Obesity is a medical condition defined as the excessive accumulation of fat that presents a risk to human health. Health hazards associated with obesity include heart disease, diabetes and cancer. Worldwide adult obesity has more than doubled since 1990, and adolescent obesity has quadrupled,” said Carlos Ibáñez of the Department of Neuroscience, Karolinska Institute, Stockholm and the IDG/McGovern Institute for Brain Research at Peking University. “Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone.”
Ibáñez explained that obesity has traditionally been described using body-mass index (BMI) however, BMI fails to distinguish individuals with similar BMI but different degrees of body fat and doesn’t correspond with comorbidities like diabetes and heart disease. “So we have moved to the body-roundness index (BRI) – a more complex measurement that takes into account different body shapes and fat accumulation, and correlates more strongly with all causes of mortality correlated with obesity.”
“For many our modern lifestyle doesn’t fit our physiology. Energy coming in is higher than the energy leaving the system,” he continued. “The problem is not in the fat itself but all the problems that arise from excessive accumulation – stroke, heart disease, diabetes, colon and liver disease and also conditions like osteoarthritis from supporting body weight.”
“It’s about the intersection of lifestyle and genetic makeup – some are obesity resistance and others obesity prone. We can control this to a certain degree but not entirely.”
“But,” he added, “major advances have taken place in the field, the best known of these being the development and clinical application of glucagon-like peptide (GLP-1) agonists.”
GLP-1 receptor agonists, of which Ozempic is one, stimulate insulin release, promote satiety and reduce energy intake. They are the most promising anti-obesity drugs thus far but do have side effects.
Ibáñez explained that GLP-1 is a peptide produced in the gut and brain. In the gut, it is produced in response to nutrients during a meal and metabolites derived from the gut microbiome. GLP-1 can decrease gastric motility, reduce inflammation and increase insulin secretion,” he explained. “This slows stomach emptying – slower digestion means less glucose is released from the food consumed. Insulin release from pancreas beta-cells is increased, and the feeling of fullness is mediated by affecting areas of brain responsible for hunger and satiety.”
He traced the long history of the development of drugs using GLP-1r agonists dating back to 1932 when hormonal activity in the gut was first identified as being responsible for insulin secretion; to the identification of GLP precursors in angelfish and the venom of the Gila monster and eventually in mammals in 1987; to approval of the first GLP-based drugs for diabetes in 2005; and, for the treatment of obesity in 2014. Hundreds of new GLP-1 based drugs are currently in clinical trials.
Suppressing ALK7
In his first STIAS residence in 2015 Ibáñez presented some of the approaches followed by his laboratory to investigate this problem, based on studies of the ALK7 protein, a highly abundant receptor molecule in rodent and human adipocytes that is a key regulator of fat metabolism and plasticity. He provided an update of this work. “We believe that strategies aimed at suppressing ALK7 activity may complement therapies based on GLP-1 agonists in the treatment of human obesity,” he said.
The work involves understanding more fully the role of the activin receptor ALK7 in adipose tissue to control metabolism, and whether blocking it could facilitate weight loss and keep it off. The normal function of ALK7 is to suppress lipolysis and lipid oxidation to preserve energy – so in a way it might be described as “the gene that helps us to get fat”.
The studies are conducted in genetically modified mice to provide proof of concept for the development of anti-obesity therapeutics based on inhibition of ALK7. In knock-out mice there is complete deletion or inactivation of a gene and in knock-in mice a specific alteration in the sequence of a gene. The knock-in and knock-out mice are compared to wild type which have no genetic changes but are inbred and therefore genetically identical.
Studies by the group have found that knock-out mice lacking ALK7 are more resistant to obesity induced by a high-fat diet. The knock-out mice show no weight gain on a normal diet and on a high-fat diet they gain weight but much less than the wild type. “There is increased lipolysis, lipid oxidation and energy expenditure in the mice lacking ALK7. So the ALK7 knock-out mice burn fat at a higher rate even on a high-fat diet,” said Ibáñez.
But what about mice that start off obese? “We can inactivate ALK7 in mice that are already obese which is a more realistic scenario for human obesity,” he explained.
“We found that the ALK7 knock out didn’t work alone in obese mice but did work when combined with changing to a low-fat diet.”
They have also investigated the introduction of anti-inflammatories. This is because in the obese state adipose tissue is very inflamed due to mechanical stress, hypoxia, free fatty acids, gut-derived substances and the activation of immune-system cells.
The addition of an anti-inflammatory – like aspirin in the case of the mice – was therefore also found to synergise with ablation of the ALK7. “Neither ALK7 knock out nor aspirin had major effects on their own but together reduced weight gain on a high-fat diet.”
Countering the Biggest Loser effect
What about people who lose weight and then regain it once returning to a normal diet? Ibáñez explained that the some of the inspiration for this work comes from the reality TV programme The Biggest Loser. “Research has shown that 70% of the participants regain the weight and some even more within six years of appearing on the show. As difficult as it is to adhere to a severe diet and exercise regime, it’s even more difficult to maintain the lost weight after the end of the weight-lowering regime.”
He explained that weight loss results in a lower resting metabolic rate, lowering the energy expenditure. Once people return to their normal eating habits with a low metabolic rate, they burn so little energy that they put weight back on.
So, could ALK7 deletion help Biggest Loser contestants maintain their lower weight?
“Our work has shown that acute ablation of ALK7 in adipose tissue of obese mice sustains the effects of lifestyle change after return to a high-fat diet. The ALK7 knock-out mice lose weight at a higher rate and gain weight at a lower rate when returned to high-fat diet.”
Ibáñez also noted that a percentage of the population naturally carries ALK7 variants and there are ongoing studies looking at the effect of these on fat distribution and BRI. “Studies have shown that people with these variants have less body fat and we have found that these variants or mutations change ALK7 function and contribute to obesity resistance in mice.”
This work is actually not far from human application since a number of pharmaceutical companies are developing ALK7 antagonists, specifically blocking antibodies, which have shown promising results in animal models and are in the first stages of clinical trials. “There is huge competition in the pharma industry in this area,” said Ibáñez. “The field is developing at blazing speed.”
In discussion, he addressed the costs of such drugs, the ethics of being able to lose weight in this way, the impact on body engineering and beauty standards, and the link between socio-economic status and obesity.
“With more options, costs will go down but may always remain high for many people,” he said.
Michelle Galloway: Part-time media officer at STIAS
Photograph: SCPS Photography