This study by Khrimian et al. demonstrates that the bone-derived hormone osteocalcin is necessary and sufficient to correct age-related cognitive decline in the mouse. It also provides genetic, molecular, and neurophysiological evidence that Gpr158 is the receptor mediating osteocalcin’s regulation of cognition.

H2A.Z is an essential histone variant implicated in the regulation of key nuclear events. However, the metazoan chaperones responsible for H2A.Z deposition and its removal from chromatin remain unknown. Here we report the identification and characterization of the human protein ANP32E as a specific H2A.Z chaperone. We show that ANP32E is a member of the presumed H2A.Z histone-exchange complex p400/TIP60. ANP32E interacts with a short region of the docking domain of H2A.Z through a new motif termed H2A.Z interacting domain (ZID). The 1.48 Å resolution crystal structure of the complex formed between the ANP32E-ZID and the H2A.Z/H2B dimer and biochemical data support an underlying molecular mechanism for H2A.Z/H2B eviction from the nucleosome and its stabilization by ANP32E through a specific extension of the H2A.Z carboxy-terminal α-helix. Finally, analysis of H2A.Z localization in ANP32E(-/-) cells by chromatin immunoprecipitation followed by sequencing shows genome-wide enrichment, redistribution and accumulation of H2A.Z at specific chromatin control regions, in particular at enhancers and insulators.

A remarkable, totally unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse since its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behavior. The regulation of cognitive function by osteocalcin, together with the fact its circulating levels decrease in midlife compared to adolescence in all species tested raised the prospect that osteocalcin may be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young WT mice. The diversity and amplitude of the functions of osteocalcin in the brain during development and postnatally had long called for the identification of its receptor in the brain, which was also recently achieved. This review presents our current understanding of osteocalcin's biology in the brain, highlighting the bony-vertebrate specificity of the regulation of cognitive function, and pointing toward where therapeutic opportunities may exist.

H2A.Z, a widely conserved histone variant, is evicted from chromatin by the histone chaperone ANP32E. However, to date, no deposition chaperone for H2A.Z is known in metazoans. Here, we identify YL1 as a specific H2A.Z-deposition chaperone. The 2.7-Å-resolution crystal structure of the human YL1-H2A.Z-H2B complex shows that YL1 binding, similarly to ANP32E binding, triggers an extension of the H2A.Z αC helix. The interaction with YL1 is, however, more extensive and includes both the extended acidic patch and the entire DNA-binding surface of H2A.Z-H2B. Substitution of only four amino acid residues of H2A is sufficient for the formation of an H2A.Z-like interface specifically recognized by YL1. Collectively, our data reveal the molecular basis of H2A.Z-specific recognition by YL1 and shed light on the mechanism of H2A.Z transfer to the nucleosome by the ATP-dependent chromatin-remodeling complexes SRCAP and P400-TIP60.

During osteoclast differentiation, two extracellular cues that induce cAMP production both converge on HDAC4 and induce Rankl expression but do so using distinct signaling pathways.

Summary Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca 2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca 2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca 2+ homeostasis, and WAT lipolysis in the regulation of energy balance.

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Despite enormous social and scientific efforts, obesity rates continue to increase worldwide. While genetic factors contribute to obesity development, genetics alone cannot explain the current epidemic. Obesity is essentially the consequence of complex genetic-environmental interactions. Evidence suggests that contemporary lifestyles trigger epigenetic changes, which can dysregulate energy balance and thus contribute to obesity. The hypothalamus plays a pivotal role in the regulation of body weight, through a sophisticated network of neuronal systems. Alterations in the activity of these neuronal pathways have been implicated in the pathophysiology of obesity. Here, we review the current knowledge on the central control of energy balance with a focus on recent studies linking epigenetic mechanisms in the hypothalamus to the development of obesity and metabolic disorders.