Obesity after neonatal overfeeding is independent of hypothalamic microgliosis

Abstract

The early-life environment is important in programming brain development, and metabolic disruptions at this time can have long-lasting effects. Previously, we have shown that rats overfed for the first 3 weeks of their neonatal life maintain obesity into adulthood. Neonatal overfeeding also leads to primed hypothalamic and hippocampal microglia that are hyper-responsive to an immune challenge in adulthood.However, whether this microglial priming contributes to the obese phenotype and whether it is possible to reverse either the obesity or the microglial priming are not clear. In the present study, we hypothesised that an intervention with minocycline during the juvenile period (postnatal day 21-42) would normalise both the microglial priming and obesity. To induce obesity in neonatal Wistar rats, we manipulated the litter sizes in which they were suckled, yielding litters of 12 (control-fed) or four (neonatally overfed). After weaning, we administered minocycline i.p. every second day for a 3-week period and examined body composition and microglial profiles 24 hours following an immune challenge with lipopolysaccharide. As demonstrated previously, neonatal overfeeding resulted in prolonged weight gain. However, minocycline failed to reverse this effect. Minocycline did reverse microglial priming in feeding-related regions of the hypothalamus, with minimal effects on pro-inflammatory cytokines and on microglial number and morphology in the hippocampus. Thus, the programming effect of neonatal overfeeding on microglial priming can be ameliorated by minocycline later in life. However, the persistent obesity seen after neonatal overfeeding is likely not driven by changes in hypothalamic inflammation and microglial activity. K E Y W O R D Shippocampus, hypothalamus, microglia, neonate, obesity

Hypothalamic inflammation in metabolic disorders and aging

“…Minocycline is another drug that was used to inhibit microglial activation and proliferation in the hypothalamus. Minocycline treatment reversed the effect of the neonatal overfeeding-induced increase in microglial numbers [373]. Further, minocycline treatment prevented the overall neuroinflammatory response in the PVN by attenuating microglial activation exerting antihypertensive effects [215,231,257].…”

Litter Size Reduction as a Model of Overfeeding during Lactation and Its Consequences for the Development of Metabolic Diseases in the Offspring

“…This phenotype can affect satiety control and could be due to early hyperinsulinemia and hyperleptinemia [ 20 ]. However, this hypothalamic microgliosis does not seem to be the major factor involved in the SL obesity phenotype [ 33 ].…”

Microglial regulation of satiety and cognition

“…Understanding of these novel roles for microglia is becoming possible because of the development of several new pharmacological and transgenic strategies for manipulating these cells. Traditional pharmacological strategies, including liposomal clodronate and minocycline, have recently been supplemented by colony‐stimulating factor 1 receptor (CSF1R) kinase inhibitors PLX3397 and PLX5562 (so far exclusively used in mice). In the transgenic space, there are now total knockouts for several microglia‐specific genes that result in the death of these cells, such as chemokine, CX3C motif, receptor 1(−/−) [cx3cr1(−/−)], complement receptor 3 [CR3(−/−)] and DAP12(−/−) .…”