The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons

Abstract

Graphical Abstract Highlights d FTO controls locomotor responses and exploration to novelty via striatal D2 MSNs d FTO regulates D2 MSN excitability and their external globus pallidus projections d Motor responses to dopaminergic activation is attenuated upon FTO loss in D2 MSNs d Mice lacking FTO in D2 MSNs are predisposed to directpathway activation SUMMARYVariations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting rewarddriven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)-or D2R-dependent pathways in these animals reveal altered responses to D1-and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty.

Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice

“…RNA extraction was performed by first homogenizing samples in 1 mL Trizol LS (Life Technologies) at 3000 rpm using estingly, with regard to neurological disease, sexual dimorphisms exist where, for example, in humans, male dominance is noted in cases of ADHD and female dominance is noted in overweight and obesity (1,58,59). Of note, we have recently shown that ablation of the obesity-associated FTO gene from postsynaptic DA neurons also manifests with increased locomotion in response to novelty in male but not female mice (60). Further research is necessary to understand how the maternal metabolic environment can result in sexually dimorphic outcomes based on the broad effects on brain development and function.…”

The role of mRNA m6A methylation in the nervous system

“…Variations in the FTO gene can not only regulate D2Rdependent reward learning [106][107][108], but also affect nerve adjust food visual, produce more frequent rewards [109][110][111], affect the control of mood and impulse [112][113][114], and affect obesity by regulating brain signaling pathways [115,116]. The homozygous mutation of FTO gene can reduce the brain capacity of healthy elderly people, increase the susceptibility to brain atrophy during aging, and even affect the brain volume of adolescents [117,118].…”

Computational analysis of the interaction of limonene with the fat mass and obesity-associated protein

“…This biochemical modification has appealed to significant attention. The association of FTO gene variation and adiposity with increased body mass has been reported in many studies [14]. Fischer et al (2009) compared the reduction of adiposity and protection from induced diet obesity by the ubiquitous inactivation of Fto and increased body mass and fat with the overexpression of FTO in mice [15].…”