circadian rhythms & the endocrine system

master biological clock

suprachiasmatic nuclei (SCN) of the hypothalamus

circadian rhythms

• endogenous/internally determined, but attuned (timing/amplitude adjusted) to external/environmental cues- dark light/dark cycles

• peripheral oscillators in most organs play key role in rhythmicity (may or may not be aligned with SCN and cues such as light, activity, or feeding)

light entrainment SCN

via retinohypothalamic tract that projects from retinal ganglion cells (specialized neurons) to SCN

small paired nuclei in hypothalamus projections/outputs to

• paraventricular nucleus (contains neurons that project to posterior pituitary, produce corticotropin-releasing hormone, or thyrotopin-releasing hormone)

• other regions of hypothalamus

• intermediolateral cell column region of spinal cord that contain sympathetic outflow fibers

SCN can control…

• physiological rhythms and coordinate or reset rhythms of peripheral oscillators by various routes

• neuronal pathways, sympathetic and parasympathetic nervous system, hormones, and changes in stimuli such as feeding rhythms

clock proteins

heterodimer of CLOCK and BMAL1 (transcription factors)

clock and BMAL1

• promote transcription of period (PER) And cryptochrome (CRY) repressor proteins

PER and CRY

• gene transcription starts in morning, finished by late afternoon

• PER and CRY proteins are formed they interact with various kinases

• translocate to nucleus to repress CLOCK-BMAL1 activity

• per and cry levels then fall because suppresion of their transcription and short half lived (degraded by proteasome)

• repressor complex turned over, so CLOCK-BLAM1 initiates new cycle of promoting PER and CRY gene transcription

REV-ERB nuclear receptors

• expression activation by CLOCK-BLAM1

• lower BMAL1 gene expression

clock controlled genes

• are in SCN, liver, heart

• circadian pacemakers in SCN & Peripheral oscillators use similar molecular machinery

• mRNAS rhythmically expressed (sometimes low amplitude)

• high degree of tissue specificity

• include genes for prohormone & neuropeptide synthesis, processing, and degradation

intrinsic liver clock

• controls metabolism of lipids and glucose

• coordinates gluconeogenesis & glucose output

• synchronized with SCN via autonomic nervous system and endocrine system

• aslo react to timing of food intake

hormone circadian rhythms

• insulin

• ghrelin

• TSH

• prolactin

• cortisol

• levels of many hormones and tissue responsiveness to hormones (receptor levels) oscillate over 24 hour period, controlled by circadian pacemaker in SCN and peripheral oscillators/clocks, feeding/fasting state, sleep/wake cycle

melatonin

• secreted by pineal gland

• chemical marker of biological night

• regulated by SCN —> sympathetic nervous system —> pineal gland, increase with hypoglycemia and darkness

• released into general circulation and cerebrospinal fluid; role in promoting sleep & Inhibiting waking, and stabilizes core temperature rhythms via its MT1 and MT2 receptors

melatonin production

• start with tryptophan, converted into serotonin

• in pineal gland serotonin undergoes a cyclic, light dependent process to be converted into melatonin

• sympathetic stimulation downstream of SCN

• binding of norepinephrine to adrenergic B1 receptors

• up regulates production of limiting enzyme that catalyzes the rate limiting step of melatonin synthesis

• no pineal storage of melatonin

melatonin across biological kingdom

• ancient signaling molecule, naturally produced in animals, plants, bacteria, fungi

• acts as antioxidant and mediates plant stress responses

• in plants might play role in interpretation of light signals such as photoperiod

• in plants and mammals the identified receptor is GPCR

• in inter-kingdom communication appears to be involved in mediating symbiotic relationships between plant root microbiome and plants

circadian rhythms and performance

• athletic performance in many types of sports exhibit circadian rhythms, with peak performance usually during late afternoon and worse performance in the morning

• early evening = wake maintenance zone when difficult to fall asleep

which hormone appears to be most regulated by the circadian cycle as opposed to behaviour

cortisol, it is following natural circadian rhythm as opposed to behaviour

how does circadian misalignment affect insulin & glucose levels across the entire cycle

• misaligned group is showing relatively high glucose levels, after eating can see these spikes in response to meals

• this is a sign of slight metabolic function, might be a sign of insulin resistance

• insulin levels are a little bit higher