Association of glycoprotein gp130 with hereditary catalepsy in mice

Glycoprotein gp130 is involved in the interleukin‐6 (IL‐6) and related cytokines' signaling. Linkage between the gp130 coding gene and freezing reaction (catalepsy) was shown. Here, we compared the expression and function of the gp130 in male mice of catalepsy‐resistant AKR/J strain and catalepsy‐prone congenic AKR.CBA‐D13Mit76 strain created by transferring the gp130 gene allele from catalepsy‐prone CBA/Lac to the genome of AKR/J strain. No difference in the gp130 expression in the frontal cortex, hippocampus and midbrain between AKR and AKR.CBA‐D13Mit76 mice was found. However, AKR.CBA‐D13Mit76 mice were more sensitive to bacterial lipopolysaccharide (LPS). The administration of LPS (50 µg/kg, ip) significantly increased mRNA level of the gene coding IL‐6‐regulated glial fibrillary acidic protein (GFAP) in the midbrain, induced catalepsy and decreased locomotion in the open field and social investigation tests in AKR.CBA‐D13Mit76, but not in AKR mice. The result indicates (1) the association between gp130 and hereditary catalepsy, (2) increased functional activity rather than expression of gp130 in AKR.CBA‐D13Mit76 mice and (3) the involvement of gp130 in the mechanism of LPS‐induced alteration of behavior.     

Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice

To investigate the role of JNK1 in metabolism, male ob/ob and diet-induced obese mice were treated with a JNK1-specific antisense oligonucleotide (ASO) or control ASO at 25 mg/kg or saline twice/wk for 6 and 7 wk, respectively. JNK1 ASO reduced JNK1 mRNA and activity by 65-95% in liver and fat tissues in both models. Compared with controls, treatment with JNK1 ASO did not change food intake but lowered body weight, fat pad weight, and whole body fat content. The treatment increased metabolic rate. In addition, the treatment markedly reduced plasma cholesterol levels and improved liver steatosis and insulin sensitivity. These positive observations were accompanied by the following changes: 1) increased mRNA levels of AR-beta(3) and UCP1 by >60% in BAT, 2) reduced mRNA levels of ACC1, ACC2, FAS, SCD1, DGAT1, DGAT2, and RBP4 by 30-60% in WAT, and 3) reduced mRNA levels of ACC1, FAS, G-6-Pase, and PKCepsilon by 40-70% and increased levels of UCP2 and PPARalpha by more than twofold in liver. JNK1 ASO-treated mice demonstrated reduced levels of pIRS-1 Ser(302) and pIRS-1 Ser(307) and increased levels of pAkt Ser(473) in liver and fat in response to insulin. JNK1 ASO-transfected mouse hepatocytes showed decreased rates of de novo sterol and fatty acid synthesis and an increased rate of fatty acid oxidation. These results indicate that inhibition of JNK1 expression in major peripheral tissues can improve adiposity via increasing fuel combustion and decreasing lipogenesis and could therefore provide clinical benefit for the treatment of obesity and related metabolic abnormalities.     

Elevated hypothalamic norepinephrine content in mice with the hereditary obese-hyperglycemic syndrome.

There is evidence that hypothalamic norepinephrine (NE) plays a role in the control of appetite in the rat. Using specific and sensitive radioenzymatic assays, we determined if there was a difference in the tissue (hypothalamus, cerebral cortex and kidney) concentration of NE or of dopamine (DA) in mice with the hereditary obese-hyperglycemic syndrome (ob/ob) and their normal weight littermates, both when they were in the rapid growth phase (2--3 months of age) and when they were mature (6--7 months of age). The concentration of NE was similar in the cerebral cortex of obese and normal mice and in the kidneys of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice and in the cerebral cortex of obese and normal mice. These observations support the concept that alterations in hypothalamic NE may play a role in the obesity of ob/ob mice.     

Genetic structure of hereditary catalepsy in mice

Catalepsy or pronounced freezing is a natural passive defense strategy in animals and a syndrome of some mental disorders in human. Hereditary catalepsy was shown to be associated with depressive-like features in rats and mice. The loci underlying the difference in predisposition to catalepsy between catalepsy-prone CBA/lacJ and catalepsy-resistant AKR/J mice were mapped using congenic line and selective breeding approaches. Three congenic mouse lines (AKR.CBA-D13Mit76C, AKR.CBA-D13Mit76A and AKR.CBA-D13Mit78) carrying the 59- to 70-, 61- to 70- and 71- to 75-c m fragments of chromosome 13 transferred from the CBA to the AKR genome were created by nine successive backcrossing of (CBA × AKR)F₁ on AKR strain. Because catalepsy was found only in the AKR.CBA-D13Mit76C and AKR.CBA-D13Mit76A mice, the major gene of catalepsy was mapped on the fragment of 61–70 c m . Selective breeding of the (CBA × (CBA × AKR))BC backcross generation for high predisposition to catalepsy showed numerous genome-wide distributed CBA-derived alleles as well as the AKR-derived alleles mapped on chromosome 17 and on the proximal parts of chromosomes 10 and 19 that increased the cataleptogenic effect of the major gene.     

Multivitamin restriction increases adiposity and disrupts glucose homeostasis in mice

A strong association between obesity and low plasma concentrations of vitamins has been widely reported; however, the causality of this relationship is still not established. Our goal was to evaluate the impact of a multivitamin restriction diet (MRD) on body weight, adiposity and glucose homeostasis in mice. The mice were given a standard diet or a diet containing 50 % of the recommended vitamin intake (MRD) for 12 weeks. At the end of the experiment, total body weight was 6 % higher in MRD animals than in the control group, and the adiposity of the MRD animals more than doubled. The HOMA-IR index of the MRD animals was significantly increased. The adipose tissue of MRD animals had lower expression of mRNA encoding adiponectin and Pnpla2 (47 and 32 %, respectively) and 43 % higher leptin mRNA levels. In the liver, the mRNA levels of Pparα and Pgc1α were reduced (29 and 69 %, respectively) in MRD mice. Finally, the level of β-hydroxybutyrate, a ketonic body reflecting fatty acid oxidation, was decreased by 45 % in MRD mice. Our results suggest that MRD promotes adiposity, possibly by decreasing adipose tissue lipolysis and hepatic β-oxidation. These results could highlight a possible role of vitamin deficiency in the etiology of obesity and associated disorders.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-014-0410-x) contains supplementary material, which is available to authorized users.     

The number of x chromosomes causes sex differences in adiposity in mice

Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the "four core genotypes," to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.     

Caspase-2 deficiency protects mice from diabetes-induced marrow adiposity

Type I (T1) diabetes is an autoimmune and metabolic disease associated with bone loss. Bone formation and density are decreased in T1-diabetic mice. Correspondingly, the number of TUNEL positive, dying osteoblasts increases in bones of T1-diabetic mice. Moreover, two known mediators of osteoblast death, TNFα and ROS, are increased in T1-diabetic bone. TNFα and oxidative stress are known to activate caspase-2, a factor involved in the extrinsic apoptotic pathway. Therefore, we investigated the requirement of caspase-2 for diabetes-induced osteoblast death and bone loss. Diabetes was induced in 16-week old C57BL/6 caspase-2 deficient mice and their wild type littermates and markers of osteoblast death, bone formation and resorption, and marrow adiposity were examined. Despite its involvement in extrinsic cell death, deficiency of caspase-2 did not prevent or reduce diabetes-induced osteoblast death as evidenced by a twofold increase in TUNEL positive osteoblasts in both mouse genotypes. Similarly, deficiency of caspase-2 did not prevent T1-diabetes induced bone loss in trabecular bone (BV/TV decreased by 30 and 50%, respectively) and cortical bone (decreased cortical thickness and area with increased marrow area). Interestingly, at this age, differences in bone parameters were not seen between genotypes. However, caspase-2 deficiency attenuated diabetes-induced bone marrow adiposity and adipocyte gene expression. Taken together, our data suggest that caspase-2 deficiency may play a role in promoting marrow adiposity under stress or disease conditions, but it is not required for T1-diabetes induced bone loss.