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Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has diverse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.

The DNA adduct levels in total white blood cells (WBC) and lymphocytes (LYM) isolated from the blood of the same individuals were evaluated using the 32P-postlabelling assay for bulky aromatic adducts. In this study, 68 male coke oven workers and 56 machines workers as a matched control were enrolled. Personal monitors were used to evaluate exposure to eight carcinogenic PAHs, including B[alpha]P, during an 8-h working shift. The exposure among coke even workers ranged widely from 0.6 to 547 micrograms/m3 and from 2 to 62,107 ng/m3, for carcinogenic PAHs and B[alpha]P, respectively. The respective values in controls were from 0.07-1.64 microgram/m3 and from 1-63 ng/m3. A significant correlation between WBC- and LYM-DNA adduct levels was found (r = 0.591, P < 0.001). DNA adduct levels in both WBC and LYM were significantly elevated in coke oven workers as compared with controls, but adduct levels were generally low (WBC: medians 2.61 vs. 1.83 LYM: 2.47 vs. 1.65 adducts/10(8) nucleotides). LYM-DNA adduct levels were significantly higher for smokers as compared with nonsmokers in both the exposed and control groups. No such differences in WBC-DNA adduct levels were observed. Positive significant correlations were found at the individual level between DNA adducts in both cell types and carcinogenic PAHs and/or B[alpha]P in the inhaled air (r = 0.38-0.45, P < 0.001). A significant correlation at the individual level between LYM-DNA adducts and urinary cotinine was also observed (r = 0.37, P < 0.001). No differences in DNA adduct levels could be attributed to GSTM1 or NAT2 genotype in either group. Nor was there any clear association of DNA adduct levels with combined GSTM1/NAT2 genotypes. The effect of personal exposure to carcinogenic PAHs on DNA adduct levels in both cell types was also investigated using a logistic regression model with adjustment for possible modulating effect of confounders (smoking, GSTM1, NAT2, age, plasma levels of vitamins A and E, body mass index and diet). The results showed that coke oven workers had a significantly (P < 0.05) increased adjusted Odds Ratio (OR = 4.2 and 3.9 for WBC and LYM-DNA adducts) for occurrence of higher DNA adduct levels as compared to controls. The results also showed that the relative risk of an increased prevalence of 'abnormal' values of DNA adduct levels was exposure-dose related. The influence of confounding variables was found not to be significant in this study of relatively limited size. In spite of this, the results suggest that the DNA adduct levels in LYM seem to be affected by smoking (OR = 1.8 for smokers) and are modulated by the influence of NAT2 genotypes (OR = 1.6 for slow acetylators). Our findings indicate that both cell types are generally suitable to monitor occupational exposure to PAHs, and the results suggest that coke oven workers, smoking individuals and slow acetylators sustain more genetic damage in their LYM-DNA from exposure to carcinogenic PAHs than individuals without these actors.