During the course of purifying nerve growth factor from the submaxillary gland of the mouse, Cohen (1960) and Levi-Montalcini and Cohen (1960) noticed that daily injections of certain gland extract fractions into newborn mice produced developmental changes that could not be ascribed to nerve growth factor. These changes included precocious opening of the eyelids (7 days compared to the usual 14 days) and a similar early eruption of the incisors. Using these gross anatomical changes as an assay, Cohen (1962) proceeded to isolate the active factor — a polypeptide which he termed epidermal growth factor (EGF).

Epidermal growth factor

The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

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Central and Peripheral Circadian Clocks in Mammals

Circadian food-anticipatory activity: formal models and physiological mechanisms

THIS REVIEW will deal with the biosynthesis of many of the members of the ACTH/lipotropin (LPH) family of peptides (Fig. 1). Peptides in this family fall into two groups: peptides related to ACTH include α-melanotropin (αMSH) and corticotropin-like intermediate lobe peptide (CLIP); peptides related to βLPH include γLPH, βMSH, and β-endorphin. In several species ACTH and βLPH each contain an identical heptapeptide segment located in the region of the molecule that is responsible for melanotropic bioactivity (1, 2). In this review we have taken a somewhat historical approach, and will therefore begin with a discussion of the biosynthesis of ACTH and the characterization of biosynthetic precursors to ACTH. When this work began, βLPH, γLPH, and βMSH were well-characterized pituitary peptides, but the opioid peptides (and β-endorphin in particular) had not yet been identified (3–5). Studies on the biosynthesis of ACTH were heavily influenced by prior work defining the biosynthetic pathways for insulin and para...

Structure and Biosynthesis of Pro-Adrenocorticotropin/Endorphin and Related Peptides*

Leptin regulation of neuroendocrine systems.

Daytime restriction of food and water availability in nocturnal animals phase shifts the circadian periodicity of plasma corticosteroid concentrations and body temperature. These shifted rhythms persist in animals with lesions of the suprachiasmatic nuclei who are arrhythmic under normal conditions. These findings suggest the existence of an additional "clock" that may be involved in the generation of the rhythm.

https://science.sciencemag.org/content/sci/197/4301/398.full.pdf

Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity

Under conditions of feeding at will and normal light-dark alternation, rats consume the major portion of their daily food intake during the dark period and the circadian peak of plasma corticosteroid concentrations and of body temperature levels occurs just prior to or subsequent to the time of light-dark transition. Both light-dark transition and time of food presentation have been implicated as “Zeitgebers” in determining the phase of these two circadian rhythms. 

The present data indicate the following: (i) The time of food presentation appears to be a more potent synchronizer of the phase of plasma corticosteroid levels than is the light-dark cycle. This has been demonstrated in rats under conditions in which light-dark phase shift has been dissociated from a concomitant shift of time of eating. In contrast, under such conditions, the rhythm of body temperature appears to be more tightly coupled to the light-dark cycle. This illustrates that the time of food ingestion and the peak of body temperature rhythms can be uncoupled and that the phasing effects of restricted food ingestion on corticosteroid rhythms does not extend to body temperature rhythms. It also suggests the presence of different control mechanisms and/or pathways for corticosteroid and body temperature rhythms as well as the use of different pathways by different Zeitgebers. (ii) Rats maintained in constant dim light with free access to food exhibit aperiodic feeding behavior; plasma corticosteroid concentrations and body temperature levels are also aperiodic. Imposition of a restricted period of food access under such constant light conditions is associated with the appearance of a circadian periodicity of both plasma corticosteroid concentrations and body temperature levels, with peaks, respectively, just before and after the time of food presentation. This represents an additional example of food entrainment of previously aperiodic functions, similar to the food entrainment we have described in animals rendered aperiodic by lesions of the suprachiasmatic nucleus.

Comparison of synchronization of circadian corticosteroid rhythms by photoperiod and food

Despite variations in plasma and/or pituitary ACTH concentrations, no changes in median eminence or medial basal hypothalamic immunoreactive ACTH-like concentrations were seen in rats studied 6 weeks posthypophysectomy,12 h or 28 days after bilateral adrenalectomy, 6 days after implantation of corticosterone pellets (75 mg), after dexamethasone administration (300 μg/100 g BW, ip, twice daily for 4 days), or after chronic immobilization stress. The lack of concordant variation of brain, pituitary, and plasma ACTH concentrations further supports the suggestion of a nonpituitary, central nervous system origin of some portion of brain immunoreactive ACTH-like activity.

Effect of stress, adrenocorticotropin or corticosteroid treatment, adrenalectomy, or hypophysectomy on hypothalamic immunoreactive adrenocorticotropin concentrations.

The concentration of epidermal growth factor (EGF) in mouse submaxillary gland displays a circadian variation, which can be phase-shifted by light-dark reversal, and which is abolished by superior cervical ganglionectomy (SCG). Such circadian variation persists in fasted animals. Peak concentrations occur during light hours, trough concentrations during dark, although peak concentrations in female animals occur 8 h in advance of the time when they are seen in male animals. The nocturnal fall can be reversed by a one hour exposure to light presented during the normal dark period. SCG does not abolish the increase in submaxillary gland EGF concentrations to levels characteristic of the normal male that is seen following testosterone administration to female mice (who normally exhibit much lower EGF concentrations). Plasma EGF concentrations do not exhibit a ciradian variation.

Circadian Periodicity of Epidermal Growth Factor and its Abolition by Superior Cervical Ganglionectomy

The effect of sympathetic denervation (bilateral superior cervical ganglionectomy) on several aspects of pituitary adrenal function was studied in 250–300g rats. Group I=Sham-op, Group 11= superior cervical ganglionectomy. (l)There was no significant difference between these groups in the plasma corticosterone (B) response to ether or immobilization stress or to ACTH administration. (2)Circadian periodicity of plasma B was determined by sequential (q.4h) tail vein sampling under LD (lights on 0800, off 2000) and under DL (lights on 2000, off 0800). Both groups showed similar peak and trough concentrations. Phase shifting occurred in both groups at day 11. (3)Compensatory adrenal hypertrophy of similar magnitude was present in both groups 10 days following unilateral adrenalectomy. These studies indicate that sympathetic input from the superior cervical ganglia is not involved in stress induced, circadian or some feedback aspects of pituitary adrenal function.

Herbert Hauser

Papers

Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity

Comparison of synchronization of circadian corticosteroid rhythms by photoperiod and food

Effect of stress, adrenocorticotropin or corticosteroid treatment, adrenalectomy, or hypophysectomy on hypothalamic immunoreactive adrenocorticotropin concentrations.

Circadian Periodicity of Epidermal Growth Factor and its Abolition by Superior Cervical Ganglionectomy

Effect of bilateral superior cervical ganglionectomy (SCG) on pituitary adrenal function in the male albino rat.