CNIC researchers discover a mechanism allowing immune cells to regulate obesity

September 17, 2020

Macrophages are immune system cells. They are essential in the early response to infections, and they also have a key role in the proper functioning of our tissues and the regulation of obesity. Now, researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have shown how this regulation unfolds in a paper published in Nature Metabolism, which could be useful to design new treatments for the obese and overweight, and for some associated pathologies, including fatty liver disease and type 2 diabetes.

The study was led by CNIC researchers directed by Dr. José Antonio Enríquez and Dr. David Sancho. It was completed in collaboration with the David Geffen School of Medicine and the Department of Medicine/Division of Cardiology of the University of California, Los Angeles (UCLA), in the US; the University of Eastern Finland and the Kuopio University Hospital (Finland); and the University of Salamanca and the Complutense University of Madrid. It explains how the activation of the mitochondrial metabolism of macrophages in response to oxidative stress due to excess nutrients contributes to fatty tissue inflammation and obesity.

"In recent decades, several studies have verified that fatty tissue macrophages facilitate an anti-inflammatory and reparative environment in normal conditions. This contributes to deactivating any processes altering the normal functioning of these tissues. These are known as anti-inflammatory or 'type M2' macrophages," Dr. Enríquez explains. However, in certain cases, he adds: "the M2 macrophages interpret that there are stress signals, normally arising in response to infection, and they foster inflammation as a defense mechanism."

These inflammation processes sourced to macrophages -says Dr. Enríquez- are responsible for the emergence of fatty tissue alterations, and "are the origin of obesity and the metabolic syndrome associated to cardiovascular disorders, fatty liver disease and type 2 diabetes." This means that, as a response to the excess nutrients created by a high-fat diet "macrophages change their function and support inflammatory processes, forming 'type M1' proinflammatory macrophages."

Mitochondrial metabolism changes

The research now published has analyzed how macrophage metabolic changes regulate this inflammatory process, which underlies obesity and the metabolic syndrome. The new findings, says Dr. Rebeca Acín-Pérez (currently at UCLA): "reveal how the detection by macrophages of oxidative danger signals -known as reactive oxygen species- leads to mitochondrial metabolism changes of these immune cells, needed to distinguish them from an M1 proinflammatory type. This oxidative stress -she clarifies- is found in morbidly obese patients, and it seems to be related to a high-fat diet, commonplace in the inadequate Western diet."

One of the conditions of this study, Dr. Sancho says, is that it proves that when this oxidative stress is reduced "it ameliorates some of the harmful parameters associated with obesity."

In previous studies, CNIC scientists had found that the Fgr protein is decisive in regulating one of the complexes of the transport chain of mitochondrial electrons -the II complex- in response to this oxidative stress, and to benefit the generation of signals (cytokines and metabolites) fostering immune responses.

Salvador Iborra says that this study "proves that this same molecular mechanism regulates the conversion process of an anti-inflammatory macrophage (M2) governing the function of the tissue to a proinflammatory macrophage (M1), where lipid droplets accumulate (Figure 1). A balance between both types of M2/M1 macrophages is crucial for the proper functioning of the body."

Although inflammation is a normal body response and it is beneficial to face acute and transitory threats, it is very damaging when it becomes persistent or chronic, even in low-grade inflammation scenarios. The researchers explain that this happens in obesity and the metabolic syndrome, and it leads to increased cardiovascular mortality and diabetes.

The information contained in this new paper proves that, in the absence of the Fgr protein, the liver increases its ability to eliminate fat by generating ketone bodies (chemical compounds produced by ketogenesis, a process using body fats as an energy source), which are eliminated in the urine, and that this further enhances the alterations of obesity to the glucose metabolism (type 2 diabetes).

The results, found in mice, have been corroborated by human cohorts, where the authors found a stark correlation of Fgr and the negative consequences of obesity.

The researchers conclude that their data suggest the potential of using specific Fgr protein inhibitors to treat obese and/or metabolic syndrome patients. The goal would be reducing the associated inflammation, thereby improving the parameters associated with these illnesses, like fatty liver and type 2 diabetes, and contributing to raise patients' life expectancy and quality.

Obesity is a major health problem, and it is involved in the development of heart diseases, cerebrovascular accidents, cancer, fatty liver disease, metabolic syndromes, high blood pressure and some autoimmune diseases. A combination of an excess intake of nutrients, a lack of physical activity and genetic risk factors leads to an imbalance of energy demanded vs. energy consumed, and this is where obesity starts. In Spain alone, it is expected that in only a decade (by 2030), there will be 27 million obese and overweight adults (80% men and 55% women).
Researchers from the Center for Biomedical Research on the Fragility and Healthy Aging Network (CIBERFES) and the Center for Biomedical Research on the Network of Cardiovascular Diseases (CIBERCV) have collaborated in the study. The study has been funded by The International Human Frontier Science Program Organization (HFSPO) (HFSP RGP0016 / 2018).About the CNIC

The Centro Nacional de Investigaciones Cardiovasculares (CNIC), directed by Dr. Valentín Fuster, is dedicated to cardiovascular research and the translation of knowledge gained into real benefits for patients. The CNIC, recognized by the Spanish government as a Severo Ochoa center of excellence, is financed through a pioneering public-private partnership between the government (through the Carlos III Institute of Health) and the Pro-CNIC Foundation, which brings together 12 of the most important Spanish private companies.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (F.S.P.)

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to