Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression

Abstract

Obesity and depression are major public health concerns, and there is increasing evidence that they share etiological mechanisms. CREB-regulated transcription coactivator 1 (CRTC1) participates in neurobiological pathways involved in both mood and energy balance regulation. Crtc1 −/− mice rapidly develop a depressive-like and obese phenotype in early adulthood, and are therefore a relevant animal model to explore possible common mechanisms underlying mood disorders and obesity. Here, the obese phenotype of male and female Crtc1 −/− mice was further characterized by investigating CRTC1’s role in the homeostatic and hedonic regulation of food intake, as well as its influence on daily locomotor activity. Crtc1 −/− mice showed a strong gender difference in the homeostatic regulation of energy balance. Mutant males were hyperphagic and rapidly developed obesity on normal chow diet, whereas Crtc1 −/− females exhibited mild late-onset obesity without hyperphagia. Overeating of mutant males was accompanied by alterations in the expression of several orexigenic and anorexigenic hypothalamic genes, thus confirming a key role of CRTC1 in the central regulation of food intake. No alteration in preference and conditioned response for saccharine was observed in Crtc1 − /− mice, suggesting that mutant males’ hyperphagia was not due to an altered hedonic regulation of food intake. Intriguingly, mutant males exhibited a hyperphagic behavior only during the resting (diurnal) phase of the light cycle. This abnormal feeding behavior was associated with a higher diurnal locomotor activity indicating that the lack of CRTC1 may affect circadian rhythmicity. Collectively, these findings highlight the male-specific involvement of CRTC1 in the central control of energy balance and circadian locomotor activity.

(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution

“…For example, Crtc1 -/- knock out mice are hyperphagic and resist towards anorexic leptin effects [6]. Male mice show alterations in hypothalamic orexigenic and anorexigenic gene expression levels [3]. Data in our initial study cohort, the human Sorbs population support CRTC1 s role on human eating behaviour (measured via the German version of the three factor eating questionnaire (FEV)) [23] while providing evidence for genetic variants affecting the eating behaviour dimensions disinhibition and hunger, but also luxury goods consumption (Table 3).…”

“…CRCT1 (CREB regulated transcription coactivator 1) belongs to the family of CREB (cAMP responsive element binding) transcriptional coactivators (CRTCs) which play critical roles in various biological processes including energy homeostasis [[1], [2], [3], [4], [5], [6]]. While CRTC2 plays a role in liver gluconeogenesis during fasting [7], CRTC3 contributes to adipocyte biology and fat distribution [8].…”

“…While CRTC2 plays a role in liver gluconeogenesis during fasting [7], CRTC3 contributes to adipocyte biology and fat distribution [8]. Most studies however focused on CRTC1 which is highest expressed in the brain, specifically in prefrontal cortex, amygdala, hippocampus, and hypothalamus, hence has a central role in regulating diverse pathways [3,9,10]. CRTC1 is involved in learning and memory formation [11,12], in pathways controlling mood [3,4], regulates longevity [10], locomotor activity [13], and also energy metabolism [3,14,15], eating behaviour and obesity and diabetes development [6,2,3,14,16,17].…”

“…CRTC1 functions as co-activator of CREB by mediating its binding to cAMP responsive elements (CREs) at target gene promoters which in turn regulates gene transcription [5]. Sensing peripheral stimuli in neurons, CRTC1 affects diverse pathways through its action in the brain [3,18]. One major driver of CRTC1 function in relation to energy metabolism is leptin [6].…”

“…Therefore, CRTC1 is an important regulator in energy sensing in brain. This is underlined by the Crtc1 −/− mouse model [3,6]. These mice represent a hyperphagic obesity phenotype while being resistant to the anorexigenic effects of leptin signaling [6].…”