From obesity to diseases of adipose tissue

A disease of adaptation to recent lifestyle trends, obesity is no longer considered a simple consequence of “gluttony”: research in recent decades has shown it to be a chronic disease associated with a disruption in the cross-talk between the adipose tissue and the rest of the body. And the factors underlying this disruption are not just related to nutrition.

Obesity and overweight presently affect 35% of adults worldwide, and the complications associated with excess weight, especially diabetes and cardiovascular disease, cause at least 2.8 million deaths each year. Since it has become a major public health problem in both wealthy and developing countries, obesity, its determinants, its consequences, its management and methods for its prevention currently constitute a research sector that is gathering momentum. However, it has not always been so.

"We owe the modern medical definition for obesity to the insurance companies," explains Arnaud Basdevant, a nutritionist and researcher*, President of the French National Obesity Plan launched in 2010. It was indeed an American insurer that, in the 1950s, first defined a threshold above which excess body fat would lead to health problems and reduce life expectancy. "However, this risk factor did not generate great interest. The disease was rare and seemed only to affect the United States. In the 1980s, the disease finally caught up with Great Britain, and then Europe. And finally, in the 1990s, this epidemic affected almost the entire planet, including many developing countries. This new medicoeconomic impact lent credibility to the disease and associated research," continues the specialist.

Adipose tissue, much more complex than originally thought

For a long time, obesity was summed up as a problem of energy balance, leading to a build-up of reserves stored in the fatty tissue. The deciphering of the mechanisms underlying this build-up owes much to the researchers at Inserm, especially the team led by Max Lafontan and Dominique Langin in Toulouse. Considered a "grease absorber" until recently, the adipose tissue has turned out to be a highly complex organ with a role that is not confined to storage. "It receives information, especially from the brain and digestive tract. It also produces many substances that constitute signals it sends to the central nervous system, liver, muscles, heart, blood vessels, intestine, etc. In an obese individual, this cross-talk is disrupted, with a two consequences: a weight drift and the occurrence of complications."

Adipocytes in culture - © Inserm, U342

Adipocytes in culture

As part of the effort, the application of modern molecular biology to the analysis of adipose tissue has led to the discovery that adipocytes, the cells that store lipids, constitute only one-third of the cells present in this tissue! The remaining cells include stem cells, cells of the immune system, vascular cells, nerve endings, etc. And as shown by many teams, especially at Inserm, adipose tissue in obese individuals is not only distinguished by its volume—it is characterised by inflammation and the production of a number of substances known as adipokines. “Inflammation leads to fibrosis, a factor of resistance in weight loss, and adipokines will generate complications in the long term,” explains Arnaud Basdevant. What triggers these disturbances remains to be understood.

A disease with multiple determinants

The identification of factors involved in the development and establishment of obesity, far from being complete, is today one of the greatest challenges in research on this pathology. Preventing the disease from developing is indeed of paramount importance if we want to stem the world epidemic.

Changes in diet and a reduction in activity undoubtedly play a role in the recent emergence of obesity. However, these nutritional factors are not enough to explain everything. Although many susceptibility genes for the disease have been discovered since 1990, the role of the environment broadly seems to be at least as important. Exposure and early events clearly have their importance, including those that occur before birth, or even before pregnancy. The influence of maternal diet, for example, is being analysed by Marie-Aline Charles in the Elfe Child Cohort Study. The role of the intestinal flora and of signals sent by the digestive tract to the adipose tissue and central nervous system is another especially promising research theme. Neurobiology is also invoked.

Of equal importance is the research conducted on the ability of adipose tissue to “recruit” new cells through the influence of certain nutrients and nervous or hormonal factors. Finally, human and social sciences are being invoked to explore the societal determinants of this disease, which especially affects individuals in vulnerable situations.

Better classification for better treatment

"Drug-based treatments for obesity remain very limited. And although surgery has undergone considerable growth, it also has its limits.Recent advances in the management of obesity are based on a more holistic approach, and take both environmental and behavioural dimensions, prevention, and treatment of complications, etc., into account," continues the clinician. A holistic and personalised approach, required when confronted by such a heterogeneous clinical entity: all the accumulated data indeed show that the repercussions of a build-up of body fat on weight depend not only on the extent of this excess, but also on its nature (degree of inflammation, size of cells, etc.), its distribution (abdominal, around the liver and heart, etc.) and associated complications, etc. The body mass index is not enough to gauge the clinical importance of obesity. "If the classification of liver and kidney pathologies had been based solely on measuring the size or weight of these organs, hepatology and nephrology would have come to a pretty pass,” ventures Arnaud Basdevant. “One must no longer speak of obesity, but of diseases of the adipose tissue:" a new classification to better describe and better manage a complex disease.

Note
* Inserm Unit U872, directed by Karine Clément, ICAN (Institute of Cardiometabolism and Nutrition) University Hospital Institute, Paris

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