22 May 2021

Searching for the biological roots of obesity

In many institutions around the world, experts are searching for the biological mechanisms underlying obesity, thus paving the way to the development of new, and more efficient, treatments. These efforts are all the more crucial because obesity, which has reached epidemic proportions worldwide, is one of the main risk factors for cancer and many other diseases.

Searching for the biological roots of obesity

The Champalimaud Centre for the Unknown, in Lisbon, is a research institution specialised in the neuroscience of behaviour and the complex interactions within biological systems, and at the same time it is a medical and technological institution providing specialised clinical treatment for oncology and mental health. In line with this, a number of its scientific teams are searching for the biological mechanisms underlying obesity, while its clinical staff is providing ongoing multidisciplinary support to patients with cancer who, after remission, are frequently at higher risk of obesity, which in turn is associated with cancer.
From the biological determinants of excessive food consumption to the effects of bariatric surgery, from the role of gut bacteria on our food choices and feeding behaviours to the subconscious “conversations” going on in our body between the digestive, the nervous and the immune systems that can give rise to obesity, from the psychological to the nutritional support afforded to patients in the clinic to fight obesity, a diversity of approaches – both scientific and clinical – is being explored. This diversity reflects the complexity of this disease, and the difficulty not only to unravel its basic mechanisms, but also to treat it and prevent it.

The pleasure of eating and excess weight

In 2018, psychiatrist and neuroscientist Albino Oliveira-Maia, head of the Neuropsychiatry Unit at Champalimaud Research and the Champalimaud Clinical Centre, published with his team and collaborators, a study on individuals with obesity in the journal Scientific Reports. They showed that hedonic hunger, a psychological measure of the drive to eat for pleasure, explains less than 10% of the variability in BMI (body-mass index, a measure of the relationship between weight and height). However, when comparing people with and without obesity, there were significant and robust differences in hedonic hunger. “While food reward clearly has a role, it is not the whole story for obesity,” Albino Oliveira-Maia said at the time.

“The pleasure of ingesting food is natural and healthy, but it becomes extreme in obesity,” added study first author Gabriela Ribeiro, a clinical nutritionist who is finishing her PhD in neuroscience in Albino Oliveira-Maia’s lab. “Obviously, to become obese, you have to ingest food in excess – and naturally, the pleasure you get from eating contributes to this excess, but our study suggests that other factors must be involved in this association.”

Albino Oliveira-Maia expanded on other potential causal factors for obesity: “Excessive high-energy food consumption and physical inactivity are important determinants of obesity, but they are in turn influenced by a wide set of biological, genetic and psychological factors, as well as the environment, social determinants and culture. Our study suggests that BMI variability can only be explained in terms of multiple factors, many of which are not yet clear.”

In a related study published this year in the American Journal of Clinical Nutrition, again led by Albino Oliveira-Maia and with Gabriela Ribeiro as the first author, the pair explored associations between hedonic hunger, among other measures, and weight loss after bariatric surgery, currently the most effective long-term treatment for severe obesity. Here they showed, for the first time, that higher hedonic hunger was associated with less weight loss, further supporting the association between this measure of food reward and obesity. However, they also found distinct associations with other measures associated with food reward:  most importantly, patients with enhanced sweet intensity perception before surgery lost more weight, rather than less. In further support of this association, those patients that experienced a greater decrease in sweet intensity ratings after surgery were also those who had greater weight loss. 

“Taken together, these two studies show that reward-related feeding behaviour is altered in obesity, which may compromise adherence, for instance, to behavioural interventions. This opens novel perspectives for understanding the underlying mechanisms contributing towards the occurrence of obesity,” says Gabriela Ribeiro.

When taste is out of the equation

In the meantime, in 2020, a study led by Albino Oliveira-Maia and neuroscientist Rui Costa (who, at that time, was responsible for labs both at Champalimaud Research and Columbia University, in New York), was published in the journal Neuron, announcing the discovery of a digestive-brain axis in mice, which is activated after the ingestion of food and controls learning of food-seeking behaviours without involving the gustatory sensors in the mouth. Through the vagus nerve (a long nerve connecting the brain to many internal organs), these two systems communicate to control food-seeking behaviours independently of how food tastes to us! 

To show this, the team developed a task in which animals would press levers to receive a direct injection of food into their stomach. “It was important to do it this way to eliminate the palatable aspects of the food and focus purely on its post-ingestive effects,” explained Ana Fernandes, a postdoctoral fellow and the first author of the study.

According to this study, at the digestive end of this axis is the liver, which may function as an overall metabolic sensor of the nutritional value of the food being eaten. At the other end, the nervous system side of this dialogue involves dopamine neurons, which are well-known components of the so-called reward circuit of the brain. “Our study shows that these neurons are also activated when a sweet treat reaches the stomach and the intestine,” said Rui Costa, not only when it reaches our taste buds.

In other words, this suggests that the human brain may learn to “feel rewarded” by food consumption through a subconscious process that doesn’t care about whether we like how the food tastes or not. Our biology is extremely powerful.

Gut microbes in control

In his Behaviour and Metabolism lab, neuroscientist Carlos Ribeiro’s research on the microbiome – the community of bacteria that resides in every animal’s gut, including human beings – also has a bearing on obesity. There’s no question that nutrients and the microbiome impact health, and diseases like obesity have been associated with the composition of the diet and the microbiome.

It so happens that, in 2017, Carlos Ribeiro and colleagues had already discovered a brain-gut “dialogue” governing feeding preferences in fruit flies. Basically, they showed that gut bacteria “speak” with the fly’s brain to control its food choices. The authors, who published their study in PLoS Biology, identified two species of bacteria that have a radical impact on animal dietary decisions. These gut bacteria “seem to induce some metabolic change that acts directly on the brain and the body,” explained Zita Santos, co-author of the study.

Later, in 2020, Carlos Ribeiro’s lab published further work on the subject in Nature Communications, showing how those two previously identified species of bacteria talk to each other to change what the fly eats. “The fly and its less complex microbiome allow us to precisely dissect the mechanisms by which the microbiota change the host’s feeding decisions,” pointed out Sílvia Henriques, first author of this study. 

What does this mean for humans? That possibly the composition of the population of those tiny microbes that are essential to our digestion may also have a say on whether we gain excess weight or not. 

Deregulation of immunity

Also at Champalimaud Research, the Immunophysiology lab, led by Henrique Veiga-Fernandes, is pursuing a totally different avenue, which involves gut immunity and might ultimately also lead to new treatments against obesity.

“The gut is home to a fascinating biological conflict between the body’s need to uptake foreign elements (nutrients) and the associated risk of exposing itself to pathogenic agents during this process,” explains Roksana Pirzgalska, a post-doc in Henrique Veiga-Fernandes lab. “The gut mucosa (the tissue membrane in contact with ingested food) is the centre stage of this conflict, with mucosal cells having to face the challenging task of coordinating nutrient absorption with immunological protection. Not surprisingly, the deregulation of mucosal function has been extensively associated with inflammatory and metabolic diseases,” such as obesity.

At the level of the gut mucosa, there are epithelial cells (lining the internal wall of the gut) and immune cells. In 2017, Henrique  Veiga-Fernandes and his team (of which Roksana Pirzgalska was not yet a member) discovered that neurons located in mucosal tissues can immediately detect an infection in the organism, promptly producing a substance that acts as an “adrenaline rush” for immune cells. Under the effect of this signal, immune cells rapidly become poised to fight the infection and repair the damage caused to surrounding tissues. Their results were published in Nature.

Since then, these researchers have complicated the “game” by hypothesising that epithelial cells in the gut also respond to brain-derived neuronal cues and that such response is a key element in the regulation of gut immunity and nutrient absorption. The search for this “brain-gut neuroepithelial circuit” is just beginning. 

“Ultimately, we aim to understand the function of this proposed circuit, and to what extent this information can be harnessed from a clinical perspective,” says Roksana Pirzgalska, namely to enable the development of new treatments of obesity. “Our hypothesis,” she adds, “is in accordance with the clinical observation that patients with obesity display a wide range of peripheral nerve complications and altered intestinal immunity. We believe that the identification and functional characterisation of this circuit will likely pave the way for new clinical approaches to obesity, among other diseases.”

Obesity and cancer 

At the Champalimaud Clinical Centre, which is devoted to oncological disease, nutritionist-dietician Marta Carriço is in charge of helping cancer survivors avoid and treat obesity by maintaining healthy dietary and lifestyle patterns. It is known that excess body fat is a risk factor for cancer recurrence, therefore tackling it is critical for long-term cancer-free survival.
Also, obesity is one of the main modifiable risk factors for cancer development. That is why Marta Carriço also provides nutritional support to people who come to the Champalimaud Clinical Centre for cancer risk assessment and early diagnosis. 

“Obesity itself causes metabolic changes that seem to be linked to cancer initiation and progression,” Marta Carriço explained in a 2020 webinar where she joined Albino Oliveira-Maia and Gabriela Ribeiro to discuss this issue. “Statistics show that, in 2030, more than 50% of the world population is expected to have obesity. Therefore some researchers believe that, by then, obesity will be the main risk factor for cancer.”

Many cancer survivors feel the urge to modify their lifestyle in order to decrease the risk of disease recurrence, diet and weight management being important factors. “We favour dietary patterns such as the Mediterranean diet, and most importantly the personalisation of our approach to each patient according to their clinical history, beliefs and daily routine,” added Marta Carriço. 

Information related to the relationship between diet, body composition and cancer should be provided to patients and, if they wish, patients should get support during the whole behavioural change journey, given that this is a complex process. “We have to get to know each patient and work together with them,” she pointed out.

“This whole approach has to be multidisciplinary,” concludes Marta Carriço, “(...) because we have to take into account not only the physical health of the patients but also their mental health,” a balance which is sometimes difficult to achieve and is at the crossroads of many different areas of expertise. Underlining the multidisciplinary nature of these efforts, Albino Oliveira-Maia and colleagues at the Neuropsychiatry Unit are involved in FAITH, a European consortium funded by a grant from the EU research and innovation programme Horizon 2020, that will study predictors of depression and quality of life in cancer survivors, including nutrition-related variables.

The diversity of the scientific and clinical approaches developed to fight obesity at the Champalimaud Centre for the Unknown mirrors the multifactorial nature of obesity. Genetic, psychological, behavioural, immunological and sensory aspects, among others, are all intermeshed in giving rise to this disease, and experts need to unravel them piece by piece to have a chance to one day develop novel and effective treatments against obesity.

By Ana Gerschenfeld, Health & Science Writer of the Champalimaud Foundation.
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