Adipocyte complement-related protein (30 kDa) (Acrp30), a secreted protein of unknown function, is exclusively expressed in differentiated adipocytes; its mRNA is decreased in obese humans and mice. Here we describe novel pharmacological properties of the protease-generated globular head domain of Acrp30 (gAcrp30). Acute treatment of mice with gAcrp30 significantly decreased the elevated levels of plasma free fatty acids caused either by administration of a high fat test meal or by i.v. injection of Intralipid. This effect of gAcrp30 was caused, at least in part, by an acute increase in fatty acid oxidation by muscle. As a result, daily administration of a very low dose of gAcrp30 to mice consuming a high-fat/sucrose diet caused profound and sustainable weight reduction without affecting food intake. Thus, gAcrp30 is a novel pharmacological compound that controls energy homeostasis and exerts its effect primarily at the peripheral level.

https://www.pnas.org/content/pnas/98/4/2005.full.pdf

Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice

Carey, Hannah V., Matthew T. Andrews, and Sandra L. Martin. Mammalian Hibernation: Cellular and Molecular Responses to Depressed Metabolism and Low Temperature. Physiol Rev 83: 1153-1181, 2003; 10....

https://www.physiology.org/doi/pdf/10.1152/physrev.00008.2003

Mammalian Hibernation: Cellular and Molecular Responses to Depressed Metabolism and Low Temperature

Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.

Melatonin as a hormone: new physiological and clinical insights

Phenology refers to the periodic appearance of life-cycle events and currently receives abundant attention as the effects of global change on phenology are so apparent. Phenology as a discipline observes these events and relates their annual variation to variation in climate. But phenology is also studied in other disciplines, each with their own perspective. Evolutionary ecologists study variation in seasonal timing and its fitness consequences, whereas chronobiologists emphasize the periodic nature of life-cycle stages and their underlying timing programmes (e.g. circannual rhythms). The (neuro-) endocrine processes underlying these life-cycle events are studied by physiologists and need to be linked to genes that are explored by molecular geneticists. In order to fully understand variation in phenology, we need to integrate these different perspectives, in particular by combining evolutionary and mechanistic approaches. We use avian research to characterize different perspectives and to highlight integration that has already been achieved. Building on this work, we outline a route towards uniting the different disciplines in a single framework, which may be used to better understand and, more importantly, to forecast climate change impacts on phenology.

/pdf/phenology-seasonal-timing-and-circannual-rhythms-towards-a-1fgkquldo7.pdf

Phenology, seasonal timing and circannual rhythms: towards a unified framework

ACRP30, a new hormone controlling fat and glucose metabolism.

Circannual control of hibernation by HP complex in the brain.

The amplitude of the early plateau phase of the action potential and the slow action potential of cardiac muscle were much lower in hibernating chipmunks than in nonhibernating chipmunks. The frequency-dependent contraction was decreased in hibernating animals but increased in nonhibernating animals. Caffeine caused a negative inotropic effect in hibernating animals but a positive inotropic effect in nonhibernating animals. Ryanodine caused greater inhibition in hibernating animals than in nonhibernating animals. These results suggest that the respective roles of the sources of calcium for cardiac excitation-contraction coupling are changed during hibernation.

Calcium source for excitation-contraction coupling in myocardium of nonhibernating and hibernating chipmunks

Expression of multiple α1-antitrypsin-like genes in hibernating species of the squirrel family

The gene for chipmunk hibernation-specific protein HP-25 is expressed specifically in the liver. To understand the transcriptional regulation of HP-25 gene expression, we isolated its genomic clones, and characterized its structural organization and 5′ flanking region. The gene spans approximately 7 kb and consists of three exons. The transcription start site, as determined by primer extension analysis, is located at 113 bp upstream of the translation initiation codon. Transient transfection studies in HepG2 cells revealed that the 80 bp 5′ flanking sequence was sufficient for the liver-specific promoter activity. In a gel retardation assay using HepG2 nuclear extracts, the 5′ flanking sequence from −74 to −46 showed a shifted band. All cDNA clones isolated by a yeast one-hybrid system for a protein capable of binding to this 5′ flanking sequence encoded HNF-4. HNF-4 synthesized in vitro bound to this sequence in a gel retardation assay. Furthermore, supershift assays with anti-(HNF-4) Ig confirmed that the protein in HepG2 or chipmunk liver nuclear extracts that bound to this sequence was HNF-4. When transfected into HeLa cells, HNF-4 transactivated transcription from the HP-25 gene promoter, and mutation of the HNF-4 binding site abolished transactivation by HNF-4, indicating that HNF-4 plays an important role in HP-25 gene expression.

HNF‐4 plays a pivotal role in the liver‐specific transcription of thechipmunk HP‐25 gene

1. To clarify the cause of uncoupling of Ca influx through Ca channels and the contractility of the myocardium in hibernating chipmunks, the electromechanical effects of two different internal Ca store inhibitors, caffeine and ryanodine, and a cardiotonic agent, isoprenaline, were investigated in papillary muscles of hibernating animals. 2. Ryanodine (10(-6) M), an inhibitor of internal Ca release, abolished the contraction with a marked inhibition of the action potential plateau (APp). In such preparations, an increase in Ca influx induced by isoprenaline (5 x 10(-8) M) failed to augment the contraction, indicating uncoupling of Ca influx and contraction. 3. In ryanodine pretreated preparations, 10 mM caffeine produced an early phase of APp, but did not affect the contraction abolished by ryanodine, while a higher concentration of caffeine (25 mM) markedly increased the contraction with an augmentation of the electrical response. 4. In the absence of ryanodine, caffeine (5 mM) almost abolished the contraction with a greater inhibition of APp. In such preparations, isoprenaline greatly increased the contraction with an augmentation of the early phase of APp. 5. These effects were not significantly affected by additional application of ryanodine, but were inhibited by nifedipine, a Ca channel blocker. 6. These observations suggest that in cardiac muscles of hibernating animals, lack of the positive inotropic effect of isoprenaline may be attributed to a rapid and effective sequestration of increased cytoplasmic Ca through Ca influx by internal stores, probably by enhancement of their ability to take up Ca.

/pdf/comparison-between-effects-of-caffeine-and-ryanodine-on-4p3d7yzi16.pdf

Noriaki Kondo

Papers

Circannual control of hibernation by HP complex in the brain.

Calcium source for excitation-contraction coupling in myocardium of nonhibernating and hibernating chipmunks

Expression of multiple α1-antitrypsin-like genes in hibernating species of the squirrel family

HNF‐4 plays a pivotal role in the liver‐specific transcription of thechipmunk HP‐25 gene

Comparison between effects of caffeine and ryanodine on electromechanical coupling in myocardium of hibernating chipmunks: role of internal Ca stores