Dietary fat: a potent microglial influencer

Abstract

Poor nutrition, lack of exercise, and genetic predisposition all contribute to the growing epidemic of obesity. Overweight/obesity create an environment of chronic inflammation that leads to negative physiological and neurological outcomes, such as diabetes, cardiovascular disease, and anxiety/depression. While the whole body contributes to metabolic homeostasis, the neuroimmune system has recently emerged as a key regulator of metabolism. Microglia, the resident immune cells of the brain, respond both directly and indirectly to dietary fat, and the environment in which microglia develop contributes to their responsiveness later in life. Thus, high maternal weight during pregnancy may have consequences for microglial function in offspring. Here, we discuss the most recent findings on microglia signaling in overweight/obesity with a focus on perinatal programming.

Keywords: circuit refinement; development; microglia; obesity; priming.

Figure 1.. TLR2 and TLR4 react to dietary fat content throughout the body.

Left Panel: PAMPs (pathogen-associated molecular patterns) such as LPS canonically activate TLR2 and TLR4, respectively. Recent literature suggests that saturated fatty acids, such as palmitic or lauric acid, augment TLR2/4 signaling. TLR2 signaling initiates through the adaptor protein MyD88 (Myeloid differentiation primary response 88) and results in activation of the transcription factors NF-KB (nuclear factor-kappaB) and AP-1 (activation protein-1) which promote transcription of pro-inflammatory genes such as TNF-α, IL-1β, and IL-6. TLR4 signaling can initiate MyD88-dependent inflammatory signaling or TRIF (TIR-domain-containing adapter-inducing interferon-β)-dependent signaling, resulting in increased expression of type I interferon genes. Center panels: In response to high-fat diet/obesity, circulating LPS levels increase, hematopoietic-derived cells promote insulin-resistance in a TLR4-dependent manner. TLR2 is upregulated in skeletal muscle and adipose tissue in response to obesity or palmitate-induced insulin resistance. TLR4 is upregulated in skeletal muscle and adipose tissue and TLR4 levels correlate with insulin resistance severity in skeletal muscle. Increased TLR2 in POMC neurons in response to high-fat diet protects against weight gain. Right panels: In response to maternal high-fat diet/obesity, Tlr4 and Cd11b are increased in the neonatal hippocampus, potentially indicative of microglial priming. Male maternal HFD offspring microglia phagocytose excess serotonin in the DRN as early as e14.5. Isolated fetal microglia from obese dams have exaggerated TNF-α production in response to LPS, though the signaling upstream of this (i.e. which TLR may be over-reactive) is unknown. The placenta shows a robust immune response to obesity/high-fat diet in humans and rodents, and both TLR2 and TLR4 likely play a role in this response. Created with BioRender.