High-saturated-fat diet-induced obesity causes hepatic interleukin-6 resistance via endoplasmic reticulum stress

Abstract

Historically, interleukin-6 (IL-6) was considered a proinflammatory cytokine contributing to the development of obesity-associated insulin resistance (1-3). However, accumulating evidence now suggests that IL-6 may contribute to the maintenance of normal systemic glucose metabolism (4-8) and that the increased circulating IL-6 concentrations during obesity may actually be an adaptive mechanism to resist obesity-associated glucose intolerance (9). One of the first reports to challenge the dogma of IL-6 as a detrimental cytokine showed that IL-6-deficient mice develop late-onset obesity and systemic glucose intolerance (10). Subsequently, it was shown that a single high-dose injection of IL-6 (400 ng) improved glucose tolerance in lean, high-fat diet (HFD)-induced obese mice, streptozytocin-induced diabetic mice, ob/ob mice, and db/db mice (7). Moreover, chronic antagonism of IL-6 worsens glucose metabolism in db/db mice (7). Together, these data strongly support a more favorable role for IL-6 in the maintenance of systemic glucose homeostasis. IL-6 may achieve some of its metabolic benefits via classical signaling in the liver, the tissue with one of the greatest concentrations of IL-6 receptors in the body, at least in mice and rats (8). This might explain why IL-6-deficient mice develop hepatic steatosis, inflammation, and insulin resistance, even when on a chow diet (11). Moreover, when the IL-6 receptor was genetically ablated specifically in the liver, mice developed hepatic inflammation, systemic glucose intolerance,

Exercise and Dairy Protein have Distinct Effects on Indices of Liver and Systemic Lipid Metabolism

“…We previously reported that SMP reduced total liver TAG content in these same obese rats . Since hepatic lipids are particularly important for liver health , we expanded on this past observation and analyzed fatty acid composition of several different lipid fractions. Here, we show that SMP, exercise, or the combination of the two interventions did not alter the relative amounts of saturated fatty acids in the TAG fraction in the liver (Figure A).…”

“…Fat accumulation in the liver, especially saturated fatty acids, can cause ER stress . At the same time, obesity‐associated hepatic steatosis is strongly linked to inflammation .…”

“…The composition of fatty acids in the liver was shown to be an important determinant of the development of dysregulated liver metabolism such as inflammation and ER stress . Despite exercise modestly reducing markers of liver lipogenesis, this was not reflected in concomitant reductions in indices of ER stress or inflammation.…”

“…Total hepatic fat content is associated with insulin resistance , but fatty acid composition (e.g., saturated or unsaturated) appears to be more important than total triglycerides (TAGs) in regard to liver health . Exercise improves liver function and reduces total hepatic lipid content , but there remains a lack of consensus on the effects of exercise on liver fatty acid composition .…”

“…We examined the effects of these interventions on the fatty acid composition of distinct hepatic lipid fractions, as well as markers of lipogenesis/fatty acid oxidation. We also assessed hepatic inflammation and endoplasmic reticulum (ER) stress, given that both were shown to be partly regulated by hepatic steatosis and lipid composition . We hypothesized that the effects of dairy and exercise would be equivalent and, when combined, would be greater than either intervention alone.…”