Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation
Authors: Ontiveros-Ángel Perla , Vega-Torres Julio David , Simon Timothy B. , Williams Vivianna , Inostroza-Nives Yaritza , Alvarado-Crespo Nashareth , Gonzalez Yarimar Vega , Pompolius Marjory , Katzka William , Lou John , Sharafeddin Fransua , De la Peña Ike , Dong Tien , Gupta Arpana , Viet Chi T. , Febo Marcelo , Obenaus Andre , Figueroa Johnny D. 
Published: April 2023

AbstractEarly life trauma and obesogenic diet effects of feeding control.Consumption of a Western-like high-saturated fat diet (WD, 42% kcal from fat) during adolescence in combination with (2) Exposure to early-life psychosocial stress leads to (3) changes in brain neurocircuitry and metabolic dysregulation. These alterations lead to (4) stress susceptibility, (5) emotional and feeding dysregulation, and (6) obesity. Dysregulation of feeding control and obesity leads to increased hedonic feeding and engages individuals in a cycle of aberrant feeding behaviors.BackgroundChildhood overweight/obesity is associated with the development of stress-related psychopathology. However, the pathways connecting childhood obesity to stress susceptibility remain poorly understood. Here, we used a systems biology approach to determine linkages underlying obesity-induced stress susceptibility.MethodsSixty-two (62) adolescent Lewis rats (PND21) were fed for four weeks with a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Subsequently, a group of rats (n= 32) was exposed to a well-established 31-day model of predator exposures and social instability (PSS). The effects of the WD and PSS were assessed with a comprehensive battery of behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), high throughput 16S ribosomal RNA gene sequencing for gut microbiome profiling, hippocampal microglia morphological and gene analysis, and gene methylation status of the stress marker, FKBP5. Parallel experiments were performed on human microglial cells (HMC3) to examine molecular mechanisms by which palmitic acid primes these cells to aberrant responses to cortisol.ResultsRats exposed to the WD and PSS exhibited deficits in sociability indices and increased fear and anxiety-like behaviors, food consumption, and body weight. WD and PSS interacted to alter indices of microstructural integrity within the hippocampal formation (subiculum) and subfields (CA1). Microbiome diversity and taxa distribution revealed that WD/PSS exposure caused significant shifts in the diversity of gut dominant bacteria and decreased the abundance of various members of theFirmicutesphylum, includingLachnospiracae NK4A136.Interestingly, the WD and PSS synergized to promote hippocampal microglia morphological and gene signatures implicated in neuroinflammation. These alterations were associated with changes in the microbiome, and in the expression and methylation status of the corticosterone receptor chaperone rat geneFkbp5. HMC3 responses to cortisol were markedly disrupted after incubating cells in palmitate, shown by morphological changes and pro-inflammatory cytokine expression and release. Notably, these effects were partly mediated by the human FKBP5 gene.ConclusionsThe combination of psychosocial stress and poor diet during adolescence has a deleterious synergistic impact on brain health. This study enhances our understanding of mechanisms and adaptations by which obesogenic environments shape the maturational trajectories of common neurobiological correlates of resilience.HighlightsObesogenic diet consumption during adolescence leads to stress-induced anxiety-like behaviors in rats.Exposure to an obesogenic environment during adolescence alters indices of hippocampal microstructural integrity.Obesogenic diet and chronic stress promote selective gut microbiota dysbiosis.Obesogenic diet and chronic stress synergize to expand putative pro-inflammatory microglia populations in the CA1 subfield of the hippocampus.Obesogenic diet and chronic stress influence hippocampalFkbp5gene methylation status at specific sites.FKBP5 integrates microglial pro-inflammatory signals under obesogenic conditions.