According to a study, published in the December issue of Cell Reports, microglia, the brain’s immune cells responsible for its response to infection or injury, may also regulate the brain’s response to diet, and, thus play a role in obesity.
Fatty acids (FAs) serve as energy substrates and as signals controlling metabolic processes.
The brain’s mediobasal hypothalamus (MBH) is able to sense fatty acids (FAs) and this process is involved in the control of food intake, thermogenesis and metabolism. In addition, Diet-induced obesity also produces metabolic inflammation in the MBH and work targeting TLR4, tumor necrosis factor α (TNF-α), NF-κB, and NLRP3.
Chronic consumption of saturated fat leads to inflammation in the adipose tissue, liver, and skeletal muscle, and in the periphery, the hallmark of this over-nutrition or ‘metabolic inflammation’ is the extensive accumulation of macrophages.
This type of inflammation also occurs in the hypothalamus, with accumulation of astrocytes and microglia, the brain’s analogs of macrophages, but it is unclear what orchestrates this process.
Metabolic inflammation in the MBH is marked by accumulation of astrocytes and microglia, the CNS analogs of macrophages. Yet, microglial responses to FAs are not understood, and tools to manipulate hypothalamic microglia have been lacking.
In the Cell Reports study a research team from UC San Francisco identifies hypothalamic microglia as sensors of saturated fat that are activated by rising levels of FAs, and that control the intensity of a highly localized form of inflammation in cases of high dietary intake. Microglial cells appear to mediate key changes in hypothalamic function that occur in response to consuming excess saturated fat, which include the reduction of the hypothalamic responsiveness to leptin, thus impacting food intake.
According to the authors, their study demonstrates that the transit of dietary SFAs into the brain is fast enough to stimulate the rapid inflammatory activation and proliferation of microglia previously reported.
Importantly, the SFA consumption induced microglial activation in the MBH despite controlling for total fat and caloric intake, and without increasing body weight. And as discussed by the authors, these data support their in vitro data, indicating that dietary SFAs directly stimulate M1 activation of MBH microglia, whereas peripheral tissue inflammation may depend, at least in part, on the presence of obesity.
Additionally, enteric SFAs induced MBH inflammation despite not increasing circulating levels of inflammatory cytokines, indicating that SFA-induced MBH inflammation is not a by-product of systemic inflammation.
Moreover, the investigators, by racking CCR2+ monocytes, were able to demonstrate that accumulation of MBH microglia in mice receiving SFA gavage was not due to infiltrating monocytes differentiating into microglia-like cells. Instead, the authors found that this accumulation is due to local proliferation in the MBH, a capacity that was inducible by depleting hypothalamic microglia using Lip-CLO or DT.
The study also provided some evidence indicating that whereas microglia sense SFA levels and transduce this into an inflammatory response, other cell types in the MBH may respond to monounsaturates.
According to Suneil Koliwad, the senior author of this study, “microglial activation in the brain may be a part of a normal physiological process to remodel brain function in response to changes in the composition of food intake”. The study also suggests that targeting hypothalamic microglia may be a promising way to mitigate diet-induced metabolic dysfunction.