Physical exercise practiced by patients submitted to bariatric surgery acts on brain regions involved in food intake, reducing hunger or accelerating satiety, for example. This was the result observed in a clinical trial conducted at Hospital das Clínicas (HC), the hospital complex run by the University of São Paulo’s Medical School (FM-USP) in Brazil. An article on the study, pointing to positive effects of exercise on obesity-related conditions in post-bariatric patients, is published in the International Journal of Obesity.

The study showed that an exercise training program starting three months after bariatric surgery produced functional alterations in brain networks associated with food intake and modified by obesity. The findings confirm the hypothesis that exercise and bariatric surgery act synergistically on the connectivity among brain regions associated with cognition, reward and emotional regulation, potentially moderating hunger and enhancing satiety.

According to the article, exercise increased the connectivity between the hypothalamus (the brain region that controls homeostasis, including regulation of appetite and energy expenditure) and the brain’s sensory areas. At the same time, it apparently decreased the link between the default mode network, which is more active during a resting state, and the salience network, the brain region involved in decision-making.

The researchers also found that exercise after bariatric surgery appeared to modulate the medial hypothalamic nucleus involved in appetite suppression and increased energy expenditure.

“The regulation of energy expenditure is governed by multiple internal and external signals. People with obesity display major dysregulation of brain regions associated with appetite and satiety. Our study showed that exercise by post-bariatric patients helped ‘normalize’ these complex networks so as to improve the central control of food intake. For example, some of these regions are activated and connect more intensely in people with obesity when they eat fatty or sugary food, increasing their desire to consume such food. We found that exercise counteracts this effect, at least in part,” Bruno Gualano, last author of the article, told Agência FAPESP. Gualano is a professor at FM-USP.

The study was supported by FAPESP via a research grant for the project “Effects of exercise training in patients undergoing bariatric surgery: a randomized clinical trial” and was part of the PhD research of Carlos Merege Filho, first author of the article, with a scholarship from FAPESP. The co-authors included Hamilton Roschel, Marco Aurélio Santo, Sônia Brucki, Claudia da Costa Leite, Maria Concepción García Otaduy and Mariana Nucci (all of whom are affiliated with HC-FM-USP); and John Kirwan of Pennington Biomedical Center (USA).

Considered one of the world’s main public health problems, obesity is a chronic disease characterized by excessive body fat accumulation and a major risk factor for cardiovascular and musculoskeletal disorders, as well as severe COVID-19. The parameter used for diagnosis in adults is body mass index (BMI), defined as weight in kilograms divided by height squared in meters. A BMI between 25 and 29.9 indicates overweight, while 30 or more signals obesity, according to the World Health Organization (WHO).

Brazil has one of the highest rates of overweight and obesity in the world. According to projections, almost 30% of the adult population will be obese in 2030. A billion people, or 17.5% of the world’s adult population, will be obese by then, according to the World Obesity Atlas 2022 published by the World Obesity Federation.

Importance

From the clinical standpoint, Gualano believes, the findings suggest that exercise should be considered an important complementary therapy to improve brain functions and enhance the known benefits of bariatric surgery, such as a reduction in cardiometabolic risk factors, as well as preservation of muscle mass and bone health.

He and his group have been conducting research in this field since 2018, as evidenced by other publications, one of which showed that exercise attenuated and reversed loss of muscle mass, improving muscle strength and function in post-bariatric patients. Genotypic and phenotypic analysis evidenced metabolic and structural remodeling of skeletal muscle.

In another study, exercise reduced risk factors for diseases associated with obesity, such as diabetes, high blood pressure and atherosclerosis (hardening of the arteries), by increasing sensitivity to insulin, combating inflammation and improving the health of blood vessels.

Methods

The randomized clinical trial reported in the International Journal of Obesity involved 30 women aged between 18 and 60 who had been submitted at HC-FM-USP’s bariatric surgery unit to a Roux-en-Y gastric bypass, which creates a small stomach pouch to restrict food intake and bypasses a large portion of the small intestine to limit calorie absorption. A majority of patients admitted to the unit are women. 

Half the study sample were randomly assigned to a six-month exercise program of resistance and aerobic training three times a week, starting three months after the operation and supervised by a team of physical education professionals.

Clinical, laboratory and brain functional connectivity parameters were assessed at the start of the trial, as a baseline, and again three and nine months after the operation. Functional magnetic resonance imaging (fMRI) was used to detect connectivity between anatomically distinct brain areas organized as networks, and to analyze the combined effects of the surgical procedure and exercise training. Data collection began in June 2018 and ended in August 2021.

“The literature has already shown that post-bariatric patients have many brain alterations compatible with improved control of appetite, satiety and hunger in neural circuits that govern food intake. Our study found that exercise training bolstered this response,” Gualano said, noting the importance of lifestyle changes to maintain the benefits of weight loss for people with obesity.

Bariatric surgery can currently be performed on patients with a BMI of between 30 and 35 and type 2 diabetes that has not been controlled for more than two years, and patients with a BMI over 35 who have other diseases associated with overweight, such as high blood pressure, sleep apnea or hepatic steatosis (fatty liver disease). For people with comorbidities, the recommended BMI is over 40.

In the past five years, 311,850 bariatric surgeries have been performed in Brazil; 14.1% were paid for by the SUS (Sistema Único de Saúde), the national health service. The rest were covered by insurance policies or paid for privately, according to the Brazilian Bariatric and Metabolic Surgery Society (SBCBM).

“Regular exercise is known to induce several physiological adaptations that translate into health benefits. These benefits are reversed if the patient stops exercising regularly. Our study didn’t measure the duration of the brain changes induced by exercise, however. They’re highly likely to diminish and possibly even go into reverse as the amount and intensity of exercise decrease. It’s crucial to adopt a healthy lifestyle in order for the responses to bariatric surgery to be long-lasting,” Gualano said.

Next steps for the research group will include studying the effects in people with obesity of exercise and diet combined with other weight loss strategies, including new drugs such as peptide analogs or incretin mimetics, a class of medications commonly used to treat type 2 diabetes. Incretins are gut hormones that aid digestion and blood sugar control by signaling to the brain to stop eating after a meal.

In early January, the National Health Surveillance Agency (ANVISA) approved semaglutide as an anti-obesity drug for long-term weight management. The drug had previously been approved only for patients with type 2 diabetes. It is the first injectable anti-obesity medication available in Brazil and is supposed to be administered once a week. It is said to enhance satiety, modulate appetite and control blood sugar. 

About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe

CeMM and Angelini Ventures are joining forces to support CeMM Principal Investigators Laura de Rooij and André Rendeiro in critical lifespan expansion initiatives leveraging a novel academic/entrepreneurial dual-track program. De Rooij and Rendeiro, in collaboration with their teams, will lead an original research program on healthy lifespan expansion.  In parallel, they will collaborate on venture creation based on scientific and business insights developed by their work. Venture creation and related business development activities will take place along with scientific research.  The expectation is that this double-track initiative will allow for virtuous feedback cycles, propelling innovation through scientific research and bold venture creation goals.

(Vienna, 22 March 2023) Some societal challenges are of such importance to assume the central stage in the public discourse on sustainability and the future of humanity. Such a challenge is aging. Aging is a multidimensional phenomenon, occurring at the individual and population levels of society and on the molecular, cellular, and organ level of the human body. The urgency of dealing with the consequences of aging is illustrated by the fact that in just over ten years from now, more than a third of the population of Italy, one of the world’s most rapidly aging countries, will be over 65 years of age. Expanding the lifespan in which individuals enjoy a healthy status, in which they can be independent and productive, is critical for economic, social, and cultural reasons.

The fundamental mechanisms of aging, at the molecular, cellular, and tissue level, are still unclear and most single theories fail to explain the phenomenon. Scientific leaders are increasingly interested in combining cutting-edge research with immediate value creation and effective societal impact. Laura de Rooij and André Rendeiro will be supported by a network of mentors and experts. At CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, the team will benefit from access to faculty peers, the center’s scientific leadership, a scientific advisory board, and the biotech ventures built in CeMM’s ecosystem of spinoffs. Through Angelini Ventures, the team will be supported to ideate and develop viable start-up companies emerging from their work and have access to an international network of investors, healthcare experts, and industry innovators.

“The Angelini Ventures team is delighted to partner with CeMM to collaborate on accelerating lifespan expansion research and venture creation. We believe this type of collaboration is the connective tissue between innovation and entrepreneurship. By combining our venture creation capabilities with the breakthrough research from CEMM, we can accelerate the pace of healthcare transformation,” says Paolo Di Giorgio, Chief Executive Officer of Angelini Ventures.

“CeMM is proud to pioneer a new training, research, and innovation method meant to foster a novel generation of professionals familiar with both the research and business worlds. In addition to expecting commercial success, the desired outcome is to create leaders able to inspire a new generation of scientists. Our goal is for the dual track of scientific research and business development to expand beyond the CeMM-Angelini network,” says CeMM Scientific Director Giulio Superti-Furga.

About the Principal Investigators

Laura de Rooij joined CeMM as principal investigator in September 2022. Her lab focuses on deciphering the transcriptomic landscape and role of circulating endothelial cells in health and aging. Laura de Rooij studied Biomedical Sciences at the University of Amsterdam (The Netherlands). She then joined the Stem Cell and Cancer Research Institute at McMaster University in Hamilton (Canada), where she studied the role of RNA binding proteins in leukemic stem cells via an in vivo two-step CRISPR-Cas9-mediated screening approach. For her post-doctoral studies, she returned to Europe to work under the mentorship of Prof. Carmeliet in the lab of Angiogenesis and Vascular Metabolism at VIB-KU Leuven (Belgium). Here she led and contributed to numerous single-cell transcriptome atlases of endothelial cells, generated from a diverse range of tissues, preclinical models, and clinical patient material in health and disease. Her studies have shed new light on the degree of vessel subtype heterogeneity in different tissues, as well as the altered composition and rewired molecular circuitries of endothelial cell subtypes in disease. Moreover, her efforts led to the discovery of previously unknown vascular subtypes and functions, including endothelial cells with a lipid-processing phenotype and potential prognostic relevance in breast cancer, and endothelial cells with a putative pro-fibrotic function in COVID-19. At CeMM, her lab focuses on deciphering the transcriptomic landscape and role of circulating endothelial cells in health and aging.
Read more about Laura de Rooij’s research

André Rendeiro is a Principal Investigator at CeMM since June 2022. He leads a group studying how cells interact to generate complex physiology in the human body, and how this changes over the lifespan of individuals and gives rise to disease. To do that, his group develops computational methods for the analysis of spatial data (spatial transcriptomics, highly multiplexed imaging, histopathological images), and its integration with various modalities of molecular, demographic, and clinical data of individuals along their lifespan. Prior to starting his group, André studied in Portugal, Austria, and Norway and earned his PhD in Molecular Medicine at CeMM in Vienna. During his PhD he developed methods for high-throughput cellular profiling and perturbation at single-cell resolution, applying them to leukemia, in the lab of Christoph Bock at CeMM. Between 2020 and 2022 he was a Postdoctoral Associate at the Institute for Precision Medicine and the Institute for Computational Biomedicine at Weill Cornell Medicine in New York. There he developed computational methods for the analysis of highly-multiplexed imaging that incorporate expression, morphology, micro-anatomy, and clinical covariates, in the lab of Olivier Elemento. He led the first tissue-level, single-cell resolution maps of lung pathology during COVID-19, and also contributed to the study of cancer, lung development, and disease, as well as COVID-19 immunology.
Read more about André Rendeiro’s research

The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international, independent, and interdisciplinary research institution for molecular medicine under the scientific direction of Giulio Superti-Furga. CeMM is oriented toward medical needs and integrates basic research and clinical expertise to develop innovative diagnostic and therapeutic approaches for precision medicine. Research focuses on cancer, inflammation, metabolic and immune disorders, and rare diseases. The Institute’s research building is located on the campus of the Medical University and the Vienna General Hospital. www.cemm.at

Angelini Ventures, the venture capital arm of Angelini Industries, is an early-stage investment firm focused on accelerating disruptive innovations and trends in digital health and life sciences. The group will invest €300M across a global portfolio led by investment professionals and advisors in Europe, North America, and Asia. Angelini Ventures has deep domain expertise and leverages a global team, advisors, and strategic partners to help entrepreneurs scale their businesses into transformative category-leading companies. www.angeliniventures.com

Angelini Industries is a multinational industrial group originally founded in Ancona (Italy) in 1919 by Francesco Angelini. Today it is a solid, structured industrial business with around 5,800 employees operating in 21 countries.  Angelini Industries operates in the health, industrial technology, and consumer goods businesses. Its investment strategy aimed at growth, constant commitment to research and development, and deep knowledge of markets and business sectors make Angelini Industries an Italian leader in the industries in which it operates.  The group is committed to reducing its environmental impact and finding increasingly cutting-edge circular economy solutions. It adopts the most advanced health and safety standards for workers and the most rigorous processes to ensure the highest quality by verifying the entire supply chain: from supplier certification to the control of raw materials, the production process, the finished product, and packaging, to spot checks at the point of sale.  For over 100 years, the Angelini family has steered the development of Angelini Industries with an entrepreneurial style typical of Italian family businesses. www.angeliniindustries.com