SUMMARY Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

SUMMARY Besides circadian rhythms, oscillations cycling with a 12h period exist. However, the prevalence, origin, regulation and function of mammalian 12h rhythms remain elusive. Utilizing an unbiased mathematical approach identifying all superimposed oscillations, we uncovered prevalent 12h gene expression and metabolic rhythms in mouse liver, coupled with a physiological 12h unfolded protein response oscillation. The mammalian 12h rhythm is cell-autonomous, driven by a dedicated 12h pacemaker distinct from the circadian clock and can be entrained in vitro by metabolic and ER stress cues. Mechanistically, we identified XBP1s as a transcriptional regulator of the mammalian 12h-clock. Down-regulation of the 12h gene expression strongly correlates with human hepatic steatosis and steatohepatitis, implying its importance in maintaining metabolic homeostasis. The mammalian 12h rhythm of gene expression also is conserved in nematodes and crustaceans, indicating an ancient origin of the 12h-clock. Our work sheds new light on how perturbed biological rhythms contribute to human disease.

Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the plasma. Mutations in G6Pase result in Von Gierke's disease (glycogen storage disease–1a), a potentially fatal genetic disorder. We have identified the transcriptional coactivator SRC-2 as a regulator of fasting hepatic glucose release, a function that SRC-2 performs by controlling the expression of hepatic G6Pase. SRC-2 modulates G6Pase expression directly by acting as a coactivator with the orphan nuclear receptor RORα. In addition, SRC-2 ablation, in both a whole-body and liver-specific manner, resulted in a Von Gierke's disease phenotype in mice. Our results position SRC-2 as a critical regulator of mammalian glucose production.

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic paralleling the increase in obesity and diabetes mellitus seen in Western diet-consuming countries. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma (HCC), an understanding of factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with fatty liver. Experimental studies have revealed several potential mechanisms by which EDC exposures might contribute to disease pathogenesis, including modulation of nuclear hormone receptor (NR) function and alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease, but for elucidating the molecular mechanisms underpinning NAFLD and the development of new prevention and treatment opportunities.