Progranulin haploinsufficiency and high-fat high-carbohydrate diet disrupt behavior and brain-gut inflammatory gene and protein networks
Maria Elizabeth de Sousa Rodrigues1, Meixiang Huang2, Sean D. Kelly1, Malú G. Tansey1 and Thomas L. Kukar2,3
1Department of Physiology, Emory University School of Medicine, Atlanta, Georgia; 2Department of Pharmacology and 3Neurology, Emory University School of Medicine, Atlanta, Georgia
Human mutations in the progranulin gene (GRN) reduce circulating levels of progranulin (PGRN) and granulins (GRNs) by half and cause frontotemporal degeneration (FTD), the most common form of early-onset dementia. In the periphery, metabolic inflammation and insulin resistance are associated with high expression of PGRN, a response which may or may not be maladaptive. Although it is accepted that exacerbated neuroinflammatory responses and behavioral impairment are features associated with PGRN deficiency, little is known about how PGRN deficiency affects metabolic parameters in energetic positive states and whether the latter affect brain function and/or behavior and increase risk for neurodegeneration. To investigate this, young adult Grn+/+, Grn+/- and Grn-/- mice were fed a standard chow diet (CD) or a high-fat high-carbohydrate (42%) (HFHC) diet ad libitum for 8 weeks after which they were assessed for sociability deficits and anxiety-like behavior, body adiposity, as well as brain and gastrointestinal pathology and inflammatory marker expression. While we found that only HFHC-fed mice displayed increased body adiposity, Grn+/- mice displayed significantly more weight gain compared WT mice independent of diet type. Grn haploinsuficiency was associated with shortening of the small intestine (indicative of gut inflammation), and HFHC diet impacted gross morphological gut parameters (decrease in colon length and cecum weight). Analyses of inflammatory and tight junction protein and mRNA expression in these tissues and in brain is ongoing. Grn-/- mice on normal chow displayed age-dependent sociability deficits; and while there was no significant difference in time spent in the center of an open-field between groups, HFHC-fed mice displayed impaired nesting behavior and Grn+/- mice fed a HFHC diet displayed increased mobility. Collectively, these results indicate that social deficits associated with Grn ablation occur in an age-dependent manner and Grn haploinsufficiency in conjunction with metabolic inflammation resulting from a HFHC diet promote social and exploratory behavioral alterations. Additional studies are warranted to understand how reductions in PGRN/GRNs in brain and peripheral tissues modulate the outcome of metabolic inflammation induced by a high-energy density diet on brain inflammation and risk for neurodegeneration.