The hypothalamic clock and its control of glucose homeostasis

Publisher Summary

Major components of energy metabolism, including feeding, thermogenesis, and glucose and lipid metabolism, show profound fluctuations along the daily light/dark (L/D)-cycle. In mammals, these periodic changes in the environment are ‘‘internalized’’ in the form of an endogenous circadian clock. In the case of energy metabolism, the biological clock output acts to synchronize energy intake and expenditure to changes in the external environment imposed by the rising and setting of the sun. According to a hypothesis, the suprachiasmatic nucleus (SCN) plays an important role in anticipating major physiological events, such as increased behavioral activity, feeding activity or sleep. This chapter employs two different research strategies to reveal the direct role played by the SCN. The first strategy involves a regular feeding schedule with six meals equispaced throughout the 24-h L/D-cycle (i.e. one standard meal every four hour) to remove the strong masking impact of the rhythmic feeding behavior and to unmask a possible direct control of the circadian clock. The second strategy involves the viral retrograde tracing technique to investigate the existence of multi-synaptic neural connections between the hypothalamic biological clock and peripheral organs such as the (endocrine) pancreas, the liver, and white adipose tissue (WAT). The chapter also presents the evidence for a direct control of the biological clock on the release of metabolic hormones, independent of the clock control on the temporal distribution of feeding behavior. Additionally, an overview of the neural mechanisms, pathways, and transmitters used by the SCN is presented to incorporate its time-of-day message into this homeostatic system.

Introduction

The awareness that the hypothalamus plays an important role in food intake, and especially its involvement in the physiology and pathology of the control of energy metabolism, dates back to 1840, when Mohr described a case of hypothalamic obesity associated with a rapid gain of body weight in a patient with a pituitary tumor (reviewed in Brobeck, 1946). It was not until 100 years later, however, that the animal experiments of Hetherington and Ranson (1940) showed that obesity resulted from lesions in the hypothalamus, independent of pituitary damage. Our understanding of the hypothalamic control of energy metabolism received a second boost some 50 years later, when the group of Friedman (Zhang et al., 1994) discovered the leptin gene, i.e. the elusive hormonal factor secreted by adipose tissue that informs the brain, and especially the hypothalamus, about peripheral fat stores. Major components of energy metabolism, including feeding, thermogenesis, and glucose and lipid metabolism, show profound fluctuations along the daily light/dark (L/D)-cycle. This periodic succession of night and day has influenced life on Earth for millions of years. In mammals, these periodic changes in the environment have been “internalized” in the form of an endogenous circadian clock. Its main function is to organize the time course of physiological, hormonal, and behavioral processes in order to allow the organism to anticipate properly these changing environmental conditions. The 24-h sleep/wake cycles are generated and orchestrated from within the hypothalamus as well. The location of the responsible biological or circadian (literally “approximately one day”) clock within the hypothalamic suprachiasmatic nuclei (SCN) was discovered in the early 1970s (Hendrickson et al., 1972; Moore and Eichler, 1972; Moore and Lenn, 1972; Stephan and Zucker, 1972). This master oscillator consists of interlocking transcriptional–translational feedback loops, and it contains both core clock genes necessary for oscillator maintenance, as well as specific output genes that impose their rhythmicity on the hypothalamus (Reppert and Weaver, 2002; Maywood et al., 2006). In the case of energy metabolism, the biological clock output acts to synchronize energy intake and expenditure to changes in the external environment imposed by the rising and setting of the sun (Ruiter et al., 2006a, Ruiter et al., 2006b).

It is thought that a circadian control of its physiology and behavior imparts survival advantages to an organism. Circadian rhythms serve to temporally partition the ecological niche and enable an organism to anticipate and adapt optimally to ambient conditions, thus maximizing the potential of the organism to survive. However, animals without a functional clockwork, either through SCN-lesions or a clock gene knock-out, do not have an obvious phenotype aside from anecdotal evidence on poor breeding (Dolatshad et al., 2006). One study in a simulated field condition suggested that arrhythmic animals are more susceptible to predation (DeCoursey et al., 1997, DeCoursey et al., 2000; DeCoursey and Krulas, 1998), and in cyanobacteria a circadian pacemaker confers a significant competitive advantage when the period of the endogenous clock resonates with the environmental L/D-cycle (Ouyang et al., 1998). However, an important aspect of circadian control may also be to time and synchronize (metabolic) processes within the organism, i.e. to optimize metabolic networks by enabling a temporal partitioning of metabolic events within and between different tissues. For example, by temporally separating chemically antagonistic reactions and by limiting the expression of certain enzymes to the time of day they are needed (Schibler and Naef, 2005).

Clearly, the most obvious target of circadian control is the behavioral sleep/wake-cycle. Question is whether a physiological process such as the rhythm in energy metabolism is gated by the behavioral rhythm or subject to an independent control of the circadian oscillator. Indeed, since in many species the temporal distribution of feeding activity is so clearly affected by the biological clock, it has been assumed that the daily rhythms in circulating concentrations of metabolic hormones and substrates, such as insulin, glucagon, leptin, glucose, and free fatty acids (FFA), are mainly induced by the behavioral rhythm, instead of being subject to a direct control of the biological clock. However, in view of the hypothesis that the SCN plays an important role in anticipating major physiological events, such as increased behavioral activity, feeding activity or sleep, we assumed a direct control of the SCN. We employed two different research strategies to reveal such a direct control of the SCN: (1) a regular feeding schedule with six meals equispaced throughout the 24-h L/D-cycle (i.e. one standard meal every 4 h) to remove the strong masking impact of the rhythmic feeding behavior and to unmask a possible direct control of the circadian clock; (2) the viral retrograde tracing technique to investigate the existence of multi-synaptic neural connections between the hypothalamic biological clock and peripheral organs such as the (endocrine) pancreas, the liver, and white adipose tissue (WAT).

The present review will present the evidence for a direct control of the biological clock on the release of metabolic hormones, independent of the clock control on the temporal distribution of feeding behavior. In addition, we will present an overview of the neural mechanisms, pathways, and transmitters used by the SCN to incorporate its time-of-day message into this homeostatic system.