A biological rhythm in the hypothalamic system links sleep-wake cycles with feeding-fasting cycles

Abstract

The hypothalamus senses the appetite-regulating hormones and also coordinates the metabolic function in alignment with the circadian rhythm. This alignment is essential to maintain the physiological conditions that prevent clinically important comorbidities, such as obesity or type-2 diabetes. However, a complete model of the hypothalamus that relates food intake with circadian rhythms and appetite hormones has not yet been developed. In this work, we present a computational model that accurately allows interpreting neural activity in terms of hormone regulation and sleep-wake cycles. We used a conductance-based model, which consists of a system of four differential equations that considers the ionotropic and metabotropic receptors, and the input currents from homeostatic hormones. We proposed a logistic function that fits available experimental data of insulin hormone concentration and added it into a short-term ghrelin model that served as an input to our dynamical system. Our results show a double oscillatory system, one synchronized by light-regulated sleep-wake cycles and the other by food-regulated feeding-fasting cycles. We have also found that meal timing frequency is highly relevant for the regulation of the hypothalamus neurons. We therefore present a mathematical model to explore the plausible link between the circadian rhythm and the endogenous food clock.

Keywords: Circadian rhythm; Diabetes; Feeding-fasting cycle; Melanocortin system; Obesity; Sleep-wake cycle.

Fig. 1

(A) The hypothalamic system with the metabotropic and the ionotropic synapses connections between neurons subpopulations (circles) of the ARC, PVH and LHA nuclei (in gray). (B) Corresponding neural circuit of the system. Two neuron subpopulations of ARC nuclei, POMC (P) and AgRP (A), and two hypothalamic nuclei, PVH (V) and LHA (L), are implicated during hormone sensing and processing. Day-night cycles are modeled by I_Circadian. The food input (F) enters the stomach (Gl₁) and then the intestine (Gl₂). The intestine influences the activity of the hormones Ghrelin (GH) and Insulin (IN). The arrows represent the excitatory and the inhibitory neurotransmissions, AgRP (red), GABA (orange), GLU (blue), α-MSH (purple), and OX (yellow). NPYR (neuropeptide Y receptor), OX-1/2 (OX-A and OX-B receptors), AChR (M3 muscarinic acetylcholine receptor), MOR (µ-opioid receptor).

Fig. 2

Hormone regulation and neuron firing patterns related to circadian rhythm and mealtime frequency, for 3 regular meals at 8, 13 and 17 h (A) and for 3 regular meals at 8, 13, 19 h plus 2 snacks at 16 and 20.5 h (B). The patterns of food intake (light gray bars), and the circadian rhythm (yellow sine function) in the top panel are the input to the dynamics of nutrients in the stomach (Gl₁) and the intestine (Gl₂) in the second and third panel, respectively. The concentrations of ghrelin, insulin and leptin fluctuate according to nutrients (solid and dashed lines) in the intestine (fourth, fifth sixth panels). The neuron firing patterns produced by POMC, AgRP, PVH and LHA, as a response to the hormones’ fluctuations, are shown in the last four panels. Dots represent experimental data.

Fig. 3

Hormone regulation and neuron patterns activities related to circadian rhythm and mealtime frequency, for 3 small meals at 8, 13 and 17 h (A) and for 2 regular meals at 13 and 17 h without breakfast (B). The patterns of food intake (light gray bars), and the circadian rhythm (yellow sine function) in the top panel are the input to the dynamics of nutrients in the stomach (black) and the intestine (gray) in the second panel. The concentrations of ghrelin (blue), insulin (red) and leptin (green) fluctuate according to nutrients (Solid lines) in the intestine (third panel). The neuron firing patterns produced by POMC, AgRP, PVH and LHA, as a response to the hormones’ fluctuations, are shown in the last panels.

Fig. 4

Hormone regulation and neuron patterns activities related to circadian rhythm and mealtime frequency during 3-days, for Time-Restricted Eating (TRE) (A) and for Common Diet (CD) (B). The patterns of food intake (light gray bars), and the circadian rhythm (yellow sine function) in the top panel are the input to the dynamics of nutrients in the stomach (black) and the intestine (gray) in the second panel. The concentrations of ghrelin (blue), insulin (red) and leptin (green) fluctuate according to nutrients in the intestine (third panel). The neuron firing patterns produced by POMC, AgRP, PVH and LHA, as a response to the hormones’ fluctuations, are shown in the last panels.