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.
Highlights
Obesity, resulting from an impairment of energy balance, represents a main public health concern because of its comorbidity with diabetes, cardiovascular diseases, cancer, and psychiatric disorders[1]
We further investigated the consequences of the lack of CREB-regulated transcription coactivator 1 (CRTC1) on the energy balance of Crtc1−/− male and female mice, with the aim of better defining CRTC1-regulated molecular pathways involved in obesity, and possibly in mood disorders as well
Crtc1−/− male mice are hyperphagic and develop obesity To characterize the obesity of Crtc1−/− mice, we monitored food intake and body weight until 36 weeks of age in males and 52 weeks in females
Summary
Obesity, resulting from an impairment of energy balance, represents a main public health concern because of its comorbidity with diabetes, cardiovascular diseases, cancer, and psychiatric disorders[1]. Clinical studies report high prevalence of obesity in patients suffering of chronic mental illnesses, and among depressive subjects, those has recently been involved in mood regulation and energy balance[6,7,8,9,10]. CRTCs can sense many external inputs, such as hormones and neurotransmitters, by detecting cytoplasmic increase of calcium and cAMP levels Upon cellular activation, they become dephosphorylated and translocate to the nucleus where they bind to CREB and activate the transcription of several tissue-specific CREB-regulated genes. A key region for regulating energy balance, CRTC1 is present in the arcuate nucleus (ARC), in the ventromedial, and in the paraventricular hypothalamus[21]
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