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

Devesh Mishra; Jennifer E. Richard; Ivana Maric; Begona Porteiro; Martin Häring; Sander Kooijman; Saliha Musovic; Kim Eerola; Lorena López-Ferreras; Eduard Peris; Katarzyna Grycel; Olesya T. Shevchouk; Peter Micallef; Charlotta S. Olofsson; Ingrid Wernstedt Asterholm; Harvey J. Grill; Ruben Nogueiras; Karolina P. Skibicka

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

2019

Summary: Chronic 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. : Mishra et al. demonstrate that IL-6 is produced by lPBN neurons, astrocytes, and microglia. They show that IL-6 acts in the lPBN to reduce body weight by increasing thermogenesis and reducing food intake. They also identify two pathophysiological/physiological contexts, obesity and cold exposure, that divergently affect lPBN IL-6 production. Keywords: lateral PBN, hindbrain, energy balance, cold exposure, obesity, thyroid, brown adipose tissue, diet-induced obesity, sex differences, PVN

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