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1. Melatonin safeguards against fatty liver by antagonizing TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner

   https://doi.org/10.1111/jpi.12611  

   Li, Dong‐Jie ; Tong, Jie ; Li, Yong‐Hua ; Meng, Hong‐Bo ; Ji, Qing‐Xin ; Zhang, Guo‐Yan ; Zhu, Jia‐Hui ; Zhang, Wen‐Jing ; Zeng, Fei‐Yan ; Huang, Gang ; et al ( October 2019 , Journal of Pineal Research)

   Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal‐regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high‐fat diet (HFD)‐induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho‐ASK1, phospho‐MKK3/6, phospho‐p38, phospho‐MKK4/7, and phospho‐JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor‐associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β‐arrestin‐1 and enabled it to bind to ASK1, which antagonized the TRAFs‐mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β‐arrestin‐1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner.

    

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2. Differential regulation of the unfolded protein response in outbred deer mice and susceptibility to metabolic disease

   https://doi.org/10.1242/dmm.037242  

   Havighorst, A. ; Zhang, Y. ; Farmaki, E. ; Kaza, V. ; Chatzistamou, I. ; Kiaris, H. ( February 2019 , Disease Models & Mechanisms)

   Endoplasmic reticulum (ER) stress has been causatively linked to the onset of various pathologies. However, if and how inherent variations in the resulting unfolded protein response (UPR) affect the predisposition to ER stress-associated metabolic conditions remains to be established. By using genetically diverse deer mice (Peromyscus maniculatus) as a model, we show that the profile of tunicamycin-induced UPR in fibroblasts isolated at puberty varies between individuals and predicts deregulation of lipid metabolism and diet-induced hepatic steatosis later in life. Among the different UPR targets tested, CHOP more consistently predicted elevated plasma cholesterol and hepatic steatosis. Compared to baseline levels or inducibility, the maximal intensity of the UPR following stimulation best predicts the onset of pathology. Differences in the expression profile of the UPR recorded in cells from different populations of deer mice correlate with the varying response to ER stress in altitude adaptation. Our data suggest that the response to ER stress in cultured cells varies among individuals and its profile early in life may predict the onset of ER stress-associated disease in the elderly. 

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3. Seasonal decrease in thermogenesis and increase in vasoconstriction explain seasonal response to N 6 ‐cyclohexyladenosine‐induced hibernation in the Arctic ground squirrel ( Urocitellus parryii )

   https://doi.org/10.1111/jnc.14814  

   Frare, Carla ; Jenkins, Mackenzie E. ; McClure, Kelsey M. ; Drew, Kelly L. ( August 2019 , Journal of Neurochemistry)

   Hibernation is a seasonal phenomenon characterized by a drop in metabolic rate and body temperature. Adenosine A₁receptor agonists promote hibernation in different mammalian species, and the understanding of the mechanism inducing hibernation will inform clinical strategies to manipulate metabolic demand that are fundamental to conditions such as obesity, metabolic syndrome, and therapeutic hypothermia. Adenosine A₁receptor agonist‐induced hibernation in Arctic ground squirrels is regulated by an endogenous circannual (seasonal) rhythm. This study aims to identify the neuronal mechanism underlying the seasonal difference in response to the adenosine A₁receptor agonist. Arctic ground squirrels were implanted with body temperature transmitters and housed at constant ambient temperature (2°C) and light cycle (4L:20D). We administered CHA (N⁶‐cyclohexyladenosine), an adenosine A₁receptor agonist in euthermic‐summer phenotype and euthermic‐winter phenotype and used cFos and phenotypic immunoreactivity to identify cell groups affected by season and treatment. We observed lower core and subcutaneous temperature in winter animals and CHA produced a hibernation‐like response in winter, but not in summer. cFos‐ir was greater in the median preoptic nucleus and the raphe pallidus in summer after CHA. CHA administration also resulted in enhanced cFos‐ir in the nucleus tractus solitarius and decreased cFos‐ir in the tuberomammillary nucleus in both seasons. In winter, cFos‐ir was greater in the supraoptic nucleus and lower in the raphe pallidus than in summer. The seasonal decrease in the thermogenic response to CHA and the seasonal increase in vasoconstriction, assessed by subcutaneous temperature, reflect the endogenous seasonal modulation of the thermoregulatory systems necessary for CHA‐induced hibernation.

   Cover Image for this issue: doi:10.1111/jnc.14528.

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4. Three daily intraperitoneal injections of sub‐anesthetic ketamine ameliorate activity‐based anorexia vulnerability of adult female mice

   https://doi.org/10.1002/eat.24036  

   Goodwin‐Groen, Sebastian ; Dong, Yiru ; Aoki, Chiye ( August 2023 , International Journal of Eating Disorders)

   To identify ketamine's dosing schedule that ameliorates voluntary food restriction, hyperactivity and body weight loss of adult mice undergoing activity‐based anorexia (ABA), an animal model of anorexia nervosa.

   Female and male C57BL6 mice underwent three cycles of ABA, starting from mid‐adolescence. ABA vulnerability was compared within and across two groups of animals: those injected intraperitoneally with 30 mg/kg ketamine for three consecutive days (30mgKetx3) during the second ABA in late adolescence (ABA2) or with vehicle only (Vx3).

   Vx3 females and males exhibited individual differences in wheel running and weight retention during first ABA in mid‐adolescence (ABA1), ABA2, and third ABA in adulthood (ABA3). Their wheel running correlated with anxiety‐like behavior. During ABA1 and ABA3, weight gain of Vx3 females (but not males) after food consumption correlated negatively with food‐anticipatory activity (FAA) preceding the feeding hours, indicating that females with higher levels of running restrict feeding more and persistently. This paradoxical relationship confirms earlier findings of ABA females without ketamine treatment, capturing the maladaptive behaviors exhibited by individuals diagnosed with anorexia nervosa. By contrast, 30mgKetx3 had an effect on both sexes of reducing hyperactivity during the feeding hours acutely and reducing anxiety‐like behavior's contribution to running. For females, only, 30mgKetx3 acutely improved the extent of compensatory food consumption relative to FAA and improved weight retention during ABA3, 12 days post ketamine in adulthood.

   Sub‐anesthetic ketamine evokes behavior‐specific ameliorative effects for adult mice re‐experiencing ABA, supporting the notion that multiple doses of ketamine may be helpful in reducing relapse among adults with anorexia nervosa.

   This study examined whether ketamine reduces anorexia‐like behaviors in adult mice. Three daily sub‐anesthetic ketamine injections suppress wheel running during and leading up to the hours of food availability and enable animals to compensate better for weight loss associated with excessive exercise by eating more. These findings suggest that ketamine may help adult females diagnosed with anorexia nervosa but also point to sex‐ and age‐related differences in the action of ketamine.

    

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5. Improvements in Metabolic Syndrome by Xanthohumol Derivatives Are Linked to Altered Gut Microbiota and Bile Acid Metabolism

   https://doi.org/10.1002/mnfr.201900789  

   Zhang, Yang ; Bobe, Gerd ; Revel, Johana S. ; Rodrigues, Richard R. ; Sharpton, Thomas J. ; Fantacone, Mary L. ; Raslan, Kareem ; Miranda, Cristobal L. ; Lowry, Malcolm B. ; Blakemore, Paul R. ; et al ( December 2019 , Molecular Nutrition & Food Research)

   Two hydrogenated xanthohumol (XN) derivatives, α,β‐dihydro‐XN (DXN) and tetrahydro‐XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet‐induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation.

   To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high‐fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance—specifically Bacteroidetes and Tenericutes—alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro‐inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host.

   Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.

    

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