RESUMEN
Our circadian world shapes much of metabolic physiology. In mice â¼40% of the light and â¼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.
Asunto(s)
Temperatura Corporal , Ritmo Circadiano , Metabolismo Energético , Fotoperiodo , Ritmo Ultradiano , Animales , Ratones , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/fisiología , Temperatura Corporal/fisiología , Ritmo Circadiano/fisiología , Metabolismo Energético/fisiología , Sueño/fisiología , Ritmo Ultradiano/fisiología , Vigilia/fisiologíaRESUMEN
Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.
Asunto(s)
Hiperfagia , Receptor de Melanocortina Tipo 4 , Humanos , Ratones , Animales , Receptor de Melanocortina Tipo 4/metabolismo , Hiperfagia/genética , Hiperfagia/metabolismo , Obesidad/metabolismo , Transducción de Señal/fisiología , MutaciónRESUMEN
A1 adenosine receptor (A1AR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure-activity relationship of 5-arylethynyl aminothiophenes as A1AR positive allosteric modulators (PAMs). The derivatives were compared in binding and functional assays at the human A1AR, indicating that some fluoro-substituted analogues have enhanced PAM activity. We identified substitution of the terminal phenyl ring in 12 (2-F-Ph), 15 (3,4-F2-Ph, MRS7935), and 21 (2-CF3-Ph) as particularly enhancing the PAM activity. 15 was also shown to act as an A1 ago-PAM with EC50 ≈ 2 µM, without activity (30 µM) at other ARs. Molecular modeling indicated that both the 5-arylethynyl and the 4-neopentyl groups are located in a region outside the receptor transmembrane helix bundle that is in contact with the phospholipid bilayer, consistent with the preference for nonpolar substitution of the aryl moiety. Although they are hydrophobic, these PAMs could provide potential drug candidate molecules for engaging protective A1ARs.