Abstract
Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.
Highlights
Obesity and type 2 diabetes mellitus (T2DM) are global chronic disorders mainly caused by a disbalance between food intake and energy expenditure [1]
To assess the changes in microglial innate immunity in the hypothalamus, following the loss of microglial Insulin receptors (InsR), we evaluated the gene expression of key genes involved in microglial function, cluster of differentiation 68 (Cd68), a commonly used phagocytic indicator in ionized calcium-binding adaptor molecule 1 (Iba1)-ir microglia; Interleukin-1 beta (Il1b) cytokine, highly produced by microglia; and inhibitor of nuclear factor-kappa b kinase subunit beta (Ikbkb), kinase involved in the phosphorylation of the inhibitor/NFkB complex, activating the nuclear factor kappalight-chain-enhancer of activated B cells (NFkB), involved in an inflammatory response
We showed that microglial insulin signaling plays a sex-dependent role in the control of systemic energy homeostasis, with microglial InsR being involved in the progression of obesity most prominently in female mice
Summary
Obesity and type 2 diabetes mellitus (T2DM) are global chronic disorders mainly caused by a disbalance between food intake and energy expenditure [1]. In the central nervous system (CNS), the hypothalamus is the key region responsible for maintaining energy homeostasis, containing neurons known to sense nutrients as well as circulating hormones [2–6]. Insulin receptors (InsR) are broadly expressed in the brain, with high concentrations in various regions, including the olfactory bulb, cerebral cortex, hippocampus, and hypothalamus [7]. Many studies have confirmed the importance of brain InsRsignaling in the regulation of food intake and energy expenditure [8–10]. Insulin affects energy homeostasis by promoting the activity of the anorexigenic proopiomelanocortin (POMC) neurons and inhibiting the activity of the agouti-related peptide/neuropeptide Y (AgRP/NPY) orexigenic neurons, promoting energy expenditure [11–14]. A key factor known to disrupt energy homeostasis and cause obesity is a hypercaloric diet [15]. Obesity is associated with low-grade chronic peripheral inflammation [16–18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
