Positional Cloning of Zinc Finger Domain Transcription Factor Zfp69, a Candidate Gene for Obesity-Associated Diabetes Contributed by Mouse Locus Nidd/SJL

Polygenic type 2 diabetes in mouse models is associated with obesity and results from a combination of adipogenic and diabetogenic alleles. Here we report the identification of a candidate gene for the diabetogenic effect of a QTL (Nidd/SJL, Nidd1) contributed by the SJL, NON, and NZB strains in outcross populations with New Zealand Obese (NZO) mice. A critical interval of distal chromosome 4 (2.1 Mbp) conferring the diabetic phenotype was identified by interval-specific congenic introgression of SJL into diabetes-resistant C57BL/6J, and subsequent reporter cross with NZO. Analysis of the 10 genes in the critical interval by sequencing, qRT–PCR, and RACE–PCR revealed a striking allelic variance of Zfp69 encoding zinc finger domain transcription factor 69. In NZO and C57BL/6J, a retrotransposon (IAPLTR1a) in intron 3 disrupted the gene by formation of a truncated mRNA that lacked the coding sequence for the KRAB (Krüppel-associated box) and Znf-C2H2 domains of Zfp69, whereas the diabetogenic SJL, NON, and NZB alleles generated a normal mRNA. When combined with the B6.V-Lepob background, the diabetogenic Zfp69SJL allele produced hyperglycaemia, reduced gonadal fat, and increased plasma and liver triglycerides. mRNA levels of the human orthologue of Zfp69, ZNF642, were significantly increased in adipose tissue from patients with type 2 diabetes. We conclude that Zfp69 is the most likely candidate for the diabetogenic effect of Nidd/SJL, and that retrotransposon IAPLTR1a contributes substantially to the genetic heterogeneity of mouse strains. Expression of the transcription factor in adipose tissue may play a role in the pathogenesis of type 2 diabetes

Obesity and cancer-extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases.

Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures

Cancer cachexia: More than skeletal muscle wasting.

Cancer cachexia is a multifactorial condition characterized by body weight loss that negatively affects quality of life and survival of patients with cancer. Despite the clinical relevance, there is currently no defined standard of care to effectively counteract cancer-associated progressive tissue wasting. Skeletal muscle atrophy represents the main manifestation of cancer cachexia. However, cancer cachexia is increasingly seen as a systemic phenomenon affecting and/or influenced by various organs. Here, we describe recent developments elucidating the roles of different tissues as well as tissue crosstalk in this wasting syndrome, including potential links to other cancer-associated morbidities. A more comprehensive understanding of cancer cachexia etiology and heterogeneity may enable the development of intervention strategies to prevent or reverse this devastating condition

Mind the Ga(b)p! – a novel hepatic gatekeeper at the switch point of metabolic homeostasis and diabetic late complications controlled by reactive metabolites.

Introduction: Type 1 and type 2 diabetes and diabetic late complications are often associated with states of chronic inflammation characterized by increased amounts of circulating reactive metabolites and proinflammatory cytokines, such as Tumor necrosis factor-alpha (TNF-α), which affect metabolic tissues by impairing physiologic hormone and nutrient signaling. So far, the molecular response to cytokine signaling in metabolic tissues, including the liver, is only marginally understood.   Results: In a screen to identify transcriptional regulators responsive to inflammatory signaling we found that the activity of the transcription factor GA-binding protein alpha (GAbpα) was reduced in response to TNF-α treatment. Our work identifies GAbp as a novel target of proinflammatory signaling in the liver and furthermore demonstrates that the TNF-α-dependent reduction in activity of the transcription factor is caused by redox-sensitive dissociation of the two subunits GAbpα and GAbpβ. Intriguingly, hepatocyte-specific ablation of GAbp activity proved to be severely atherogenic in LDLRko mice, due to perturbed lipid homeostasis.   Conclusions: As TNF-α and reactive metabolites, including ROS are characteristically increased in metabolic disorders, the TNF-α-dependent ROS-mediated repression of GAbp activity provides a molecular link between inflammation and diabetic derailment. We will further investigate the role of this exceptional regulatory mechanism for diabetic late complications associated with increased proinflammatory signaling, oxidative stress and reactive metabolites. We believe that our novel insights into the interplay of inflammation, ROS and metabolic disorders will provide a new toehold for potential innovative treatment options.   Achnowledgements: Supported by the SFB1118-Reactive metabolites as cause for diabetic complications to S.H. and P.N.

Seasonal changes of myostatin expression and its relation to body mass acclimation in the Djungarian hamster, Phodopus sungorus.

The Djungarian hamster is an animal that is prominent for distinct seasonal adaptations. Cued by shortening day length in autumn they spontaneously exhibit reductions in food intake, body mass (BM), fat mass and also in lean mass (LM). The mechanisms behind the seasonal regulation of body composition are only partly resolved. Although most studies focused on the participation of body fat in seasonal body weight regulation, we addressed the influence of LM, moreover of muscle mass (MM) on seasonal BM changes. Therefore, we analyzed body composition, MM and the expression of myostatin, a hormone negatively regulating muscle growth and differentiation, in Djungarian hamsters in response to naturally changing photoperiod in winter compared to long photoperiod (LP). Winter-acclimated hamsters upregulated myostatin mRNA when compared with hamsters adapted to natural and artificial LP, whereas MM remained unchanged when compared with natural LP. Moreover, in natural short photoperiod, individual myostatin expression levels were negatively correlated with MM. These results suggest that myostatin is under seasonal control in order to regulate MM and hence contributes to the overall LM and therefore BM changes in seasonal mammals

Effects of periodic intake of a high-caloric diet on body mass and leptin resistance

The effects of continuous or intermittent access to a high-caloric (HC) diet, always offered in addition to standard chow, on body mass and leptin resistance were analyzed in female C57BL/6J mice. Susceptibility for diet-induced obesity (DIO) was apparent from the marked preference for the HC diet. Continuous HC diet feeding of mice at 4 weeks of age induced leptin resistance within 2 weeks and massive gains in body mass, although with increasing inter-individual variability in the inbred strain considered to be isogenic. In adult mice receiving HC diet for the first time, leptin treatment failed to reduce energy intake first after 11 days of HC diet feeding, but became effective again within 3 days after HC diet withdrawal. In mice with a history of several preceding periods of access to the HC diet totalling >30 days, supplementary HC diet abolished the anorectic effect of leptin treatment within only 3 days and it reappeared not earlier than 11 days after HC diet withdrawal. Thus, in the investigated DIO-prone mouse strain both, the loss of responsiveness to leptin under HC diet and its recovery after HC diet withdrawal strongly depended on the dietary history. Recovery from leptin resistance during periods of intermittent chow feeding was associated with losses of body mass that did not completely compensate for the obesity-inducing effect of the preceding HC diet