The role of the SCN clock in the regulation of leptin signaling in the brain

Project Description:

There is an alarming rate of growing incidence of metabolic disorders including obesity and Type2 Diabetes (1). Many scientific studies report that the risks of developing such diseases is enhanced by lifestyle changes which promote circadian misalignment (3,4). Mammals harbor a ubiquitous circadian clock system with a master pacemaker located in Suprachiasmatic nucleus (SCN) of Hypothalamus. The output time of the molecular clock in SCN is set to approx. 24 hrs by retinal light input which is the most vital timing cue (zeitgeber) for entrainment. Out of the other zeitgebers, the second most important is the food intake which is mediated by various factors and hormones including ghrelin, leptin, adiponectin and insulin. Insulin is a hormonal regulator of appetite that increases rapidly after a meal. It is able to penetrate the blood-brain barrier via a receptor-mediated process. When insulin enters into the brain (through Insulin receptors: IR’s), it acts as anorexigenic signal giving a feeling of satiety that decreases the food intake. IR’s in brain are at higher concentrations in olfactory bulb, hypothalamus, cerebral cortex, cerebellum and hippocampus (5). In hypothalamus, Arcuate nucleus (Arc) is the centre of appetite regulation. It has two major neuronal populations: one is located medially and co-expresses Neuropeptide Y (NPY) and Agouti-related protein (AgRP) that act as orexigenic signal, increase hunger and hence, increase food intake. The other is located peripherally and co-expresses Cocaine and Amphetamine related transcripts (CART) and Pro-opiomelanocortin (POMC) (precursor of α-melanocyte stimulating hormone (αMSH)) that act as anorexigenic signals, suppressing hunger, hence reducing food intake. Changes in the expression of theses hypothalamic neuropeptides are pivotal mechanisms mediating insulin’s anorexigenic effects in the CNS (5). We are interested in studying whether these effects of CNS insulin are time-bound. A study by Schwartz M. et al, 1992 and Benoit SC et. Al, 2002, stated that administration of insulin in the third ventricle of the brain decreases expression of the orexigenic NPY and increases the expression of POMC in Arc. This results in suppression of hunger and decrease in food intake. It would be interesting to see whether there would be difference in effects when insulin is administered at different time points of the active/inactive phases. We hypothesize that the difference in time-points of central insulin action may lead to difference in food intake, thereby suggesting that there is a circadian control in insulin action of appetite regulation. Studying circadian control of central insulin action is important for reasons, one including the fact that mechanisms underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding (that occurs in irregular meal times or shift work) disrupts circadian physiology which is associated with increased prevalence of metabolic diseases like Type2 Diabetes and obesity.

  1. Kalsbeek A, la Fleur S, Fliers E. Circadian control of glucose metabolism. Molecular metabolism. 2014;3:372–383.
  2.  Kiehn J-T, Tsang AH, Heyde I, Leinweber B, Kolbe I, Leliavski A, et al. Circadian rhythms in adipose tissue   physiology. Comprehensive Physiology. 2011;7:383–427.
  3. Dibner C, Schibler U. Circadian timing of metabolism in animal models and humans. Journal of internal medicine. 2015;277:513–527.
  4. Lemmer B, Oster H. The role of circadian rhythms in the hypertension of diabetes mellitus and the metabolic syndrome. Current hypertension reports. 2018;20:43.
  5. Leona Plum, Bengt Belgardt, Jens Bruning.  Central insulin action in energy and glucose homoestasis. The Journal of Clinical Investigation. 2006: 1761-1766