Inflammation during obesity is not all bad: evidence from animal and human studies

Abstract

Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes.

Fig. 1.

Hypoxia as a common root for various changes in adipose tissue in obesity. ER, endoplasmic reticulum. Hypoxia can induce complex changes in the endocrine and metabolic phenotype of the adipose tissue.

Fig. 2.

Impact of proinflammation and anti-inflammation events in adipose tissue on glucose homeostasis in peripheral tissues. Obesity and adipose tissue expansion and remodeling activate both proinflammation and anti-inflammation events. Expression of proinflammatory cytokines (leptin, IL-1, TNF-α, IL-6, IL-18, etc.) is enhanced in adipocytes, macrophages, and lymphocytes. To control chronic inflammation, the anti-inflammation molecules (ADPN, IL-1Ra, IL-10, etc.) are activated to balance the inflammatory impact. Both the pro- and anti-inflammatory events occurring in adipose tissue spill over onto peripheral tissues to alter insulin resistance and energy expenditure. The anti-inflammatory molecules tend to promote energy (fat and glucose) storage and improve insulin action, whereas the proinflammatory activities facilitate weight loss yet impair insulin action. A: on balance, the impact of glucose homeostasis is an integration of the pro- and anti-inflammatory activities. B: upon removal of proinflammation, the balance of homeostasis can be compromised due to loss of the beneficial increase in energy expenditure.