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.
Subramanian V, Ferrante AW Jr.
Nestle Nutr Workshop Ser Pediatr Program. 2009;63:151-9; discussion 159-62, 259-68. doi: 10.1159/000209979.
High levels of IKKε and TBK1 also resulted in lower levels of a second messenger molecule called cAMP, which increases energy expenditure by elevating fat burning.
Amlexanox interfered with the two enzymes and restored sensitivity to catecholamine, allowing the fat cells to burn energy.
In research published in February 2013, Saltiel found that amlexanox reversed obesity, diabetes and fatty liver in mice. The forthcoming eLife paper explains in part how amlexanox works.
Inflammatory mechanisms in obesity
The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.
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Gregor MF, Hotamisligil GS.
Annu Rev Immunol. 2011;29:415-45. doi: 10.1146/annurev-immunol-031210-101322
“There is considerable evidence to suggest that in states of obesity, adipose tissue becomes less sensitive to catecholamines because IKKε and TBK1 act as a sort of brake on metabolism, and that this reduced sensitivity in turn reduces energy expenditure,” Saltiel said. “By releasing the brake, amlexanox seems to free the metabolic system of mice to burn more and possibly store less energy in response to catecholamines.”
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Saltiel is the Mary Sue Coleman Director of the Life Sciences Institute, where his laboratory is located and all his research is conducted. He is also the John Jacob Abel Collegiate Professor in the Life Sciences and a professor of internal medicine and molecular and integrative physiology at the Medical School.
Other authors of the paper are Jonathan Mowers, Maeran Uhm, Shannon Reilly, Joshua Simon, Dara Leto, Shian-Huey Chiang and Louise Chang, all from U-M. Support for the research was provided by the Michigan Diabetes Research and Training Center.
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Laura J. Williams
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734-615-4862
University of Michigan