Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism

Abstract

SummaryChronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6.

Effects of IL-6 Signaling Pathway Inhibition on Weight and BMI: A Systematic Review and Meta-Analysis

“…With regards to IL-6’s effects on the CNS, there is some evidence indicating that IL-6 might lead to weight loss through a reduction in food intake and/or appetite suppression. For example, in animal studies, where IL-6 was administered intracerebroventricularly, it led to a suppression of food intake, whereas when IL-6 was administered at the same dose intraperitoneally there was no effect on food intake [ 40 , 41 ]. Mishra et al [ 41 ] have postulated that IL-6 exerts its anorexigenic effects through interaction with leptin.…”

“…For example, in animal studies, where IL-6 was administered intracerebroventricularly, it led to a suppression of food intake, whereas when IL-6 was administered at the same dose intraperitoneally there was no effect on food intake [ 40 , 41 ]. Mishra et al [ 41 ] have postulated that IL-6 exerts its anorexigenic effects through interaction with leptin. Another possible mechanism by which IL-6 could be exerting food intake/appetite control is through its effects on hypothalamic neuropeptides such as neuropeptide Y, agouti-related peptide, melanin-corticotrophin-releasing hormone and pro-opiomelanocortin [ 13 ].…”

“…found that IL-6 increases glucose disposal in healthy humans [ 45 , 49 ]. Additionally, IL-6 deficient mice develop mature-onset obesity, partially attributed to reduced energy expenditure [ 15 ], and conversely, overexpression of IL-6 leads to increased thermogenesis [ 41 ] energy expenditure [ 11 ].…”

Understanding the Role of Interleukin-6 (IL-6) in the Joint and Beyond: A Comprehensive Review of IL-6 Inhibition for the Management of Rheumatoid Arthritis

“…In animal studies, IL-6 -/ -mice develop spontaneous mature-onset obesity, increased body weight, SC fat, and dysregulation of glucose metabolism [105]. Furthermore, centrally administered IL-6 (into the parabrachial nuclei) reduces food intake and increases brown adipose tissue thermogenesis in lean and obese rats (by increasing thyroid and sympathetic outflow to the adipocytes), and interacts with leptin to reduce feeding [106].…”

Immunometabolic Changes in Glia – A Potential Role in the Pathophysiology of Obesity and Diabetes

“…In addition to activation by leptin, STAT3 can be phosphorylated through signal transduction downstream of the interleukin (IL)-6 receptor (IL-6R). IL-6 is an important pleiotropic cytokine implicated in the central regulation of energy and glucose homeostasis ( Wallenius et al, 2002 , Timper et al, 2017 , Mishra et al, 2019 ). IL-6 and its receptor are produced and expressed by both astrocytes and microglia ( Erta et al, 2012 ).…”