Valdearcos, M. | Search bioRxiv

bioRxiv2024

Microglia mediate the early-life programming of adult glucose control

Mammalian glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for the formation of synapses between hypothalamic glucoregulatory centers. Although microglia are known to prune synapses throughout the brain, their specific role in refining hypothalamic glucoregulatory circuits remains unknown. Here, we show that microglia in the mediobasal hypothalamus (MBH) of mice actively engage in synaptic pruning during early life. Microglial phagocytic activity is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In particular, we show that microglia refine perineuronal nets (PNNs) within the neonatal MBH. Indeed, transiently depleting microglia before weaning (P6-16), but not afterward (P21-31), remarkably increased PNN abundance in the MBH. Furthermore, mice lacking microglia only from P6-16 had glucose intolerance due to impaired glucose-responsive pancreatic insulin secretion in adulthood, a phenotype not seen if microglial depletion occurred after weaning. Viral retrograde tracing revealed that this impairment is linked to a reduction in the number of neurons in specific hypothalamic glucoregulatory centers that synaptically connect to the pancreatic {beta}-cell compartment. These findings show that microglia facilitate synaptic plasticity in the MBH during early life through a process that includes PNN refinement, to establish hypothalamic circuits that regulate adult glucose homeostasis.

physiology↗

bioRxiv2022

Microglial inflammatory activation paradoxically improves glucose tolerance during diet-induced obesity

Hypothalamic gliosis associated with high fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain, and is therefore presumed to promote obesity-associated consequences such as glucose intolerance as well. Nevertheless, the body weight-independent contribution of microglial activation to glucose regulation has not been determined. Here we show that reducing microglial NF-{kappa}B signaling via cell-specific IKK{beta} deletion exacerbates HFD-induced glucose intolerance and insulin resistance despite reducing body weight and adiposity. This effect was associated with reduced activity of hypothalamic glucose sensing neurons. Conversely, a genetic approach to increase microglial inflammatory activity improved glucose tolerance independently of diet in lean rodents. To avoid confounding effects due to chronic alterations to microglial signaling pathways from dietary or genetic interventions, we developed an inducible model of microglial activation using DREADD-based chemogenetics. Gq-coupled GPCR activation rapidly increased microglial calcium levels, cytokine gene expression, and morphological hallmarks of inflammatory activation. In both lean and obese rodents, chemogenetic microglial activation caused a marked improvement in glucose tolerance along with increased activation of hypothalamic glucose sensing neurons, effects abrogated by central blockade of TNF signaling. Thus, while diet-induced microglial activation promotes weight gain, it may also serve an adaptive function--to prevent the deterioration of glucose tolerance associated with obesity, an important consideration for immune-modulating metabolic therapies.

neuroscience↗