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Obesity and type 2 diabetes are associated with chronic inflammation response in the adipose tissue, in which macrophage activation and infiltration are hallmark characteristics. However, the molecular mechanism of this association remains largely unknown. Here, we show that CREB/ATF bZIP transcription factor CREBZF as a critical regulator of the adipose macrophage sensing inflammatory signals to cause systemic insulin resistance in obesity. We found that CREBZF was markedly induced in bone-marrow-derived macrophages and J774 macrophage cell lines in response to lipopolysaccharide treatment. To elucidate the function of CREBZF, we generated a myeloid cell-specific CREBZF knockout (CREBZF MKO) mouse by crossing floxed CREBZF mice with LysM-Cre transgenic mice. Myeloid cell-specific CREBZF deficiency in mice largely attenuated high-fat high sucrose (HFHS) diet-induced obesity and insulin resistance and hyperglycemia. CREBZF MKO mice showed a dramatic reduction of infiltrated macrophages in the white adipose tissue and an induction of whole-body energy expenditure. Ablation of CREBZF in myeloid cells caused a potent reduction of M1 macrophages and a concomitant induction of M2 macrophages in the adipose tissue of mice fed with HFHS diet, suggesting an important role of CREBZF in regulating adipose tissue macrophage polarization. Interestingly, CREBZF is capable of potentiating NF-κB signaling as evidenced by increased phosphorylation of IκB and p65 in the macrophage, whereas CREBZF deficiency resulted in opposite effects. These data indicate that CREBZF plays an important role in the regulation of innate immune response in the macrophage, and maintains whole-body energy metabolism and glucose homeostasis. Pharmacologic manipulation of CREBZF activity in the macrophage may provide novel opportunities for treating obesity, insulin resistance and type 2 diabetes. Disclosure: Z. Hu: None. Y. Liu: None. Z. Liu: None. Z. Zhao: None. A. Cui: None. F. Ma: None. Y. Xue: None. Y. Han: None. F.F. Zhang: None. J. Fan: None. Y. Li: None. Funding: National Key Research and Development Program of China (2017YFC0909601); National Natural Science Foundation of China (31471129, 31671224); Chinese Academy of Sciences (KJZD-EW-G20-02); K.C. Wong Education Foundation (to Y.L.) [ABSTRACT FROM AUTHOR]

Obesity is becoming a worldwide pandemic. Interfacial engineering of food lipid is expected to inhibit diet-induced obesity without damage to the eating enjoyment brought by high-fat diets. Unfortunately, this strategy has not been achieved yet. After screening different plant proteins, bromelain and papain were found to form wormlike and long-straight protein fibrils, respectively. The conversion of long-straight amyloid-like fibrils to wormlike fibrils was demonstrated in the fibrillation of bromelain. Using oil-in-water high internal phase emulsions (HIPEs) as a proof of concept, bromelain fibrils showed dramatically stronger interfacial stabilization capabilities than papain fibrils with high application potentials in the real-world formulation of high-fat food products such as mayonnaise. Compared with papain fibrils, oral administration of HIPEs stabilized by bromelain fibrils resulted in substantially higher fecal lipid contents and significantly decreased expression levels of the genes related to lipid absorption and transport in the intestine, including CD36 , FATP-2 , FATP-4, and APOA-4 , without a difference in intervening gut microbiota. Consequently, dramatically less lipid absorption in the small intestine, markedly smaller chylomicron particles in the plasma, lower serum triglycerides, and controlled energy and lipid metabolism, as well as the inhibition of adipose expansion and overweight, were observed in the group with gavage of HIPEs stabilized by the bromelain fibrils rather than the papain fibrils. Furthermore, with the same calorie, substitution of all the fat in the standard high-fat feed of mice with the HIPEs emulsified by the bromelain fibrils showed a significantly stronger effect than the ones prepared by the papain fibrils on preventing high-fat-diet (HFD)-induced obesity including alleviation of adipose expansion and inflammation as well as fatty liver, also via inhibiting the absorption and transport of lipid in the intestine. The effect is ascribed to the suppressed lipolysis caused by a more compact and elastic interfacial layer formed by the wormlike fibrils than that of the long-straight fibrils, which are resistant to gastric environments and replacement by bile acids in digestion. Therefore, we provide an appealing and general strategy for controlling obesity by reducing the supply of free fatty acids (FAs) for absorption in the enteric lumen through protein fibril polymorphisms at the interface.

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.

Autophagy is of key importance for eliminating aggregated proteins during the maintenance of cellular proteostasis in response to endoplasmic reticulum (ER) stress. However, the upstream signaling that mediates autophagy activation in response to ER stress is incompletely understood. In this study, in vivo and in vitro approaches were utilized that include gain- and loss-of-function assays and mouse livers and human cell lines with tunicamycin-induced pharmacological ER stress. We report that calreticulin, a quality control chaperone that binds to misfolded glycoproteins for refolding in the ER, is induced under ER stress. Calreticulin overexpression stimulated the formation of autophagosomes and increased autophagic flux. Interestingly, calreticulin was sufficient for attenuating ER stress in tunicamycin- or thapsigargin-treated HeLa cells, whereas lentivirus-mediated shRNA calreticulin knockdown exacerbated ER stress. Mechanistically, we noted that calreticulin induces autophagy by interacting with microtubule-associated protein 1A/1B-light chain 3 (LC3). Confocal microscopy revealed that the colocalization of calreticulin and LC3 at the autophagosome was enhanced under ER stress conditions. Importantly, a conserved LC3-interacting region was necessary for calreticulin-mediated stimulation of autophagy and for reducing ER stress. These findings indicate a calreticulin-based mechanism that couples ER stress to autophagy activation, which, in turn, attenuates cellular stress, likely by alleviating the formation of aberrantly folded proteins. Pharmacological or genetic approaches that activate calreticulin-autophagy signaling may have potential for managing ER stress and related cellular disorders., (© 2018 Yang et al.)