SON-light activation of glucose regulation

Abstract

Body temperature maintenance is an important regulator of glucose homeostasis. In this issue of Cell, Meng et al. (2022) discover a novel regulatory axis in which light activation of photoreceptive retinal ganglia stimulates the supraoptic nucleus to inhibit brown adipose tissue thermogenesis and impair glucose homeostasis.

Preview

Blood glucose levels are tightly regulated by glucose uptake and storage in the fed state, and release of stored glucose from the liver in the fasted state. To achieve glucose homeostasis, the body integrates external cues of nutrient availability and energy demand, including the environmental temperature. The brown adipose tissue (BAT), which is densely packed with mitochondria containing uncoupling protein 1 to disrupt the potential energy of the proton gradient and generate heat, responds to decreased external temperature by increasing glucose uptake by 12-fold (Orava et al., 2011). The capacity for glucose uptake in the BAT may hold therapeutic potential for type 2 diabetes, but more information is needed on the normal regulation of BAT activity to harness its glucose disposal for the treatment of metabolic disease (Cypess et al., 2009; Cypess et al., 2015).

In addition to ambient temperature, the BAT is also regulated by circadian entrainment. As light enters the eye and hits the retina, 150 million photoreceptors are activated. Most photoreceptor cells are rods and cones that sense light through photopigments, such as rhodopsin in rods and iodopsin in cones. Approximately 300 photoreceptors are a specialized class of intrinsically photosensitive retinal ganglion cells (ipRGCs) involved in non-image forming functions such as neuroendocrine regulation and circadian rhythms (Duda et al., 2020). The suprachiasmatic nucleus (SCN) in the hypothalamus is activated by ipRGC stimulation to control the production of melatonin, a hormone that regulates sleep/wake cycles, and set peripheral clocks including in the liver and adipose tissue. Circadian control of these peripheral clocks synchronizes energy expenditure with energy availability to coordinate cell division, lipid metabolism, and glucose homeostasis. One mechanism by which the SCN sets the peripheral clocks is through control of body temperature, activating BAT via the circadian nuclear receptor Rev-Erbα (Buhr et al., 2010; Gerhart-Hines et al., 2013). Dyssynchrony between the central clock in the SCN and peripheral clocks of the body is associated with high rates of metabolic disease including type 2 diabetes. Further exploration is needed to understand how the mechanisms and external signals that regulate this dyssynchrony affect glucose homeostasis in type 2 diabetes.

In this issue of Cell, Meng et al. discover a new mechanism of BAT thermogenesis by light, via activation of the supraoptic nucleus (SON) rather than the SCN. The mapping of this regulatory axis began with the observation that light activation of ipRGCs elevated blood glucose and impaired glucose clearance. Using several mouse knockout models, the authors found that this activation of the ipRGCs was through the photopigment melanopsin, encoded by the Opn4 gene. OPN4 is a G-protein coupled receptor that undergoes a conformational shift with blue light, triggering depolarization through opening of transient receptor potential ion channels. Fluorescent reporter mapping of this neuronal activation and innervation determined that this signal travels to both the SCN and SON. However, only ablation of the SON led to a loss of glucose clearance with light activation of ipRGCs. Using this mapping and ablation strategy Meng et al. chased the neuronal signal from the SON to the paraventricular nucleus (PVN), then through the GABAergic neurons in the solitary trace nucleus (NTS), and then to the rostral raphe pallidus (RPa), which directly regulates BAT function. The authors determined that this SON/BAT axis is responsible for light-mediated impairment of glucose homeostasis.

There is also evidence that the SON/BAT axis regulates human health. Meng et al quantified glucose uptake in adult humans showing that the increased glucose uptake in darkness is conserved, and that it is dependent on activation of ipRGC activation by blue wavelength light. In thermoneutrality, the improved glucose homeostasis in the dark was lost, suggesting dependence on thermogenic adipose tissue in humans. These findings have striking results for our highly regulated modern society which lives at a thermoneutral state with constant exposure to light.

Despite this meticulous mapping of the SON/BAT axis, more work is needed to better understand the regulation of BAT in this system. In cold induced thermogenesis, BAT is activated when norepinephrine binds to β−3 adrenergic receptors (β3ARs). β3AR is a G-protein coupled receptor that initiates a signal transduction cascade through protein kinase A resulting in lipolysis, activation of UCP1 in the mitochondria by free fatty acids, and transcriptional activation of thermogenic genes in the nucleus. The SON/BAT axis is dependent on β3AR activation since thermoneutrality, β3AR inhibitors, denervation, and β3AR knockout mice do not have worsened glucose regulation with light exposure. However, the regulation of β3AR in this system remains elusive. Norepinephrine is not the only brain derived activator of BAT, there are also natriuretic peptides and BMP proteins secreted from neurons that innervate the tissue (Liu et al., 2018). Future work exploring these signals in the context of the SON/BAT axis is warranted.

Several questions remain about the functional role of the SON/BAT axis in the normal regulation of glucose homeostasis. One possibility is that the SON/BAT axis represents a tight regulatory point, acting to shut off thermogenesis in response to rapid shifts in external temperature associated with light such as the temperature increases coinciding with sunrise, or the immediate cold felt entering a dimly lit cave. Because these stimuli are transient but require rapid physiological adjustment, the SON/BAT axis would be an advantageous response. The interplay between the SON and SCN for glucose homeostasis remains completely unexplored. The SON/BAT axis could underlie previously assumed circadian physiology such as the ‘dawn phenomenon’―the surge of glucose that is observed in the early morning in humans preceding breakfast (Peng et al., 2022). The dawn phenomenon causes misdiagnosis of type 2 diabetes due to the elevated glucose levels in the fasted state and the input of the SON on glucose clearance in this system should be explored. As our society continues to ingest a high sugar diet, in a state of constant light expsoure, and in thermoneutrality, the interplay between these environmental signals may hold the answer to the rise in type 2 diabetes rates.

Figure 1. Light modulation of brown fat activity.

Top panel: When light is detected by intrinsically photosensitive retinal ganglion cells (ipRGC) located in the retina, a conformational change occurs in the photopigment melanopsin (OPN4) leading to its activation, GTP attachment to the G_α subunit leading to translocation and binding to Phospholipase C (PLC). PLC then cleaves phosphatidylinositol 4,5-bisphosphate (PIP₂) to inositol triphosphate (IP₃) and diacylglycerol (DAG) to activate ion channels for depolarization to generate an action potential down the neuron where it innervates and activates the supraoptic nucleus (SON) (not shown). This signal goes through several more areas of the brain before it is finally transduced to the brown adipose tissue (BAT) where it inhibits β3AR dependent glucose uptake and thermogenesis.

Bottom panel: In the absence of light, the signal from the ipRGCs is not activated and leads to a loss of inhibition on β3AR dependent glucose uptake and thermogenesis in BAT.