Ablation of the Id2 Gene Results in Altered Circadian Feeding Behavior, and Sex-Specific Enhancement of Insulin Sensitivity and Elevated Glucose Uptake in Skeletal Muscle and Brown Adipose Tissue

Abstract

Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our earlier studies have demonstrated a role for ID2 in the input pathway, core clock function and output pathways of the mouse circadian system. We have also reported that Id2 null (Id2−/−) mice are lean with low gonadal white adipose tissue deposits and lower lipid content in the liver. These results coincided with altered or disrupted circadian expression profiles of liver genes including those involved in lipid metabolism. In the present phenotypic study we intended to decipher, on a sex-specific basis, the role of ID2 in glucose metabolism and in the circadian regulation of activity, important components of energy balance. We find that Id2−/− mice exhibited altered daily and circadian rhythms of feeding and locomotor activity; activity profiles extended further into the late night/dark phase of the 24-hr cycle, despite mice showing reduced total locomotor activity. Also, male Id2−/− mice consumed a greater amount of food relative to body mass, and displayed less weight gain. Id2−/− females had smaller adipocytes, suggesting sexual-dimorphic programing of adipogenesis. We observed increased glucose tolerance and insulin sensitivity in male Id2−/− mice, which was exacerbated in older animals. FDG-PET analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue of male Id2−/− mice, suggesting increased glucose metabolism and thermogenesis in these tissues. Reductions in intramuscular triacylglycerol and diacylglycerol were detected in male Id2−/− mice, highlighting its possible mechanistic role in enhanced insulin sensitivity in these mice. Our findings indicate a role for ID2 as a regulator of glucose and lipid metabolism, and in the circadian control of feeding/locomotor behavior; and contribute to the understanding of the development of obesity and diabetes, particularly in shift work personnel among whom incidence of such metabolic disorders is elevated.

Id transcriptional regulators in adipogenesis and adipose tissue metabolism

“…Only ~20% of mice escape from death but they are severely growth retarded (44, 50). These Id2 −/− mice displayed several metabolic phenotypes such as increased glucose tolerance, insulin sensitivity, reduced gonadal WAT, altered daily and circadian rhythms of feeding and locomotor activity, and increased energy expenditure (51). Although some of the observed metabolic phenotypes could be attributed to severe growth defects in Id2 −/− mice, it cannot be excluded that lack of Id2 could also have direct impact on adipose tissue metabolism.…”

High fat diet rescues disturbances to metabolic homeostasis and survival in theId2null mouse in a sex-specific manner

“…The generation and husbandry of Id2 −/− mice, and determination of genotypes, was performed as described previously [7,9]. Id2+/+ wild-type (WT) and Id2 −/− mice were on a mixed background for breeding purposes: 129sv/C57BL6J/FBVN [7,9].…”

“…Moreover, studies have shown that absence of Id2 results in impaired adipogenesis in vitro and that Id2 −/− mice have reduced gonadal white adipose tissue (WAT) and lipid content in the liver [3,4]. Our previous findings demonstrated that Id2−/− mice exhibit altered feeding and locomotor rhythms, sex- and age-dependent enhanced glucose tolerance and insulin sensitivity, and sex-dependent elevated glucose uptake in skeletal muscle and brown adipose tissue [9]. It is well known that risk, development and manifestation of obesity, metabolic syndrome and insulin-resistance are sexually dimorphic [10,11].…”

Cukrzyca w społeczeństwie 24/7. Związek między pracą zmianową a zaburzeniami metabolicznymi

“…Aktywność tego centralnego zegara biologicznego regulowana jest przede wszystkim światłem. SCN poprzez wpływ na czynniki humoralne, autonomiczny układ nerwowy i termoregulację narzucają organizmowi "wystandaryzowany" czas lub, inaczej mówiąc, synchronizują molekularne zegary biologiczne w tkankach i komórkach obwodowych [23,24] w celu optymalizacji funkcji życiowych i dopasowania metabolizmu do zachowania organizmu: spożywania pokarmu, zwiększonej aktywności fizycznej, czuwania i snu [14]. Wpływają na produkcję melatoniny, ale także podlegają jej wpływo-wi, co stanowi jedno z wielu istotnych dla utrzymania cykliczności życia sprzężeń zwrotnych [17].…”

“…Praca zmianowa i ograniczenie snu [14,24] prowadzą do spadku stężenia leptyny i zwiększonego apetytu [14,24]. Wśród osób wykonujących PZ po posiłku stężenie greliny (hormon łaknienia) obniża się mniej, a stężenie kseniny (hormonu sytości) mniej wzrasta w porównaniu z grupą kontrolną [14,34].…”