Breaking the cycle of obesity, inflammation and disease

Researchers at University of Michigan have illuminated an aspect of how the metabolic system breaks down in obesity. The findings provide additional evidence that a drug entering clinical trials at the university could reverse obesity, Type 2 diabetes and fatty liver disease in humans.

In a paper scheduled for online publication in the journal eLife on Dec. 24, Alan Saltiel, the Mary Sue Coleman Director of the Life Sciences Institute, explains how, in obesity, fat cells stop responding to hormones known as catecholamines that trigger them to expend more energy. However, the fat cells of obese mice treated with a drug called amlexanox regained sensitivity to catecholamines, burned the excess energy and returned to normal size.

Next month, scientists at U-M will begin a placebo-controlled clinical trial of amlexanox to test its efficacy as a drug for treating obesity and diabetes in humans. Formulations of amlexanox are prescribed in different international markets to treat asthma and canker sores.

Obesity leads to a state of chronic, low-grade inflammation in liver and fat tissue. Scientists believe that inflammation links obesity and insulin resistance via a pathway called NFkB, which is involved in the regulation of a range of cellular processes and activated in obesity.

Activation of NFkB increases the levels of a pair of genes, IKKε and TBK1, which in turn reduce the ability of certain receptors in the fat cells of obese mice to respond to catecholamines like adrenaline, "fat-burning" hormones generated by the sympathetic nervous system in response to stress.

"We've suspected that in obesity, fat cells become less sensitive to catecholamines such as adrenaline, and that this reduced sensitivity in turn reduces energy expenditure, but the details of this haven't been fully understood," Saltiel said.

Obesity, inflammation, and macrophages The World Health Organization estimates that since 1980 the prevalence of obesity has increased more than threefold throughout much of the world, and this increase is not limited to developed nations. Indeed, the incidence of obesity is increasing most rapidly among rapidly industrializing countries raising the spectre of a burgeoning epidemic in obesity-associated diseases, including diabetes, dyslipidemia, nonalcoholic fatty liver disease and atherosclerosis. Reducing the rates of obesity and its attendant complications will require both coordinated public health policy and a better understanding of the pathophysiology of obesity. Obesity is associated with low grade chronic inflammation, a common feature of many complications of obesity that appears to emanate in part from adipose tissue. In obese individuals and rodents adipose tissue macrophage accumulation is a critical component in the development of obesity-induced inflammation. The macrophages in adipose tissue are bone marrow-derived and their number is strongly correlated with bodyweight, body mass index and total body fat. The recruited macrophages in adipose tissue express high levels of inflammatory factors that contribute to systemic inflammation and insulin resistance. Interventions aimed at either reducing macrophage numbers or decreasing their inflammatory characteristics improves insulin sensitivity and decreases inflammation. Macrophage accumulation and adipose tissue inflammation are dynamic processes under the control of multiple mechanisms. Investigating the role of macrophages in adipose tissue biology and the mechanisms involved in their recruitment and activation in obesity will provide useful insights for developing therapeutic approaches to treating obesity-induced complications.