Report on the Status of Payday Lending in California

Provides an overview of storefront and Internet payday lending in California, its effects, state and federal laws and regulations, and reform efforts. Includes recommendations for state and local policy, banking access, and consumer education

Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1(d/-) mice

Background: Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function. Methods: ERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans andmice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1(d/-) mice, which model a human progeroid syndrome. Results: Ercc1(d/-) mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivitywas increased, whereas, plasma insulin levelswere decreased in Ercc1(d/-) mice. Fasting induced hypoglycemia in Ercc1(d/-) mice, whichwas the result of increased glucose disposal. Ercc1(d/-) mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1(d/-) mice. Islets isolated from Ercc1(d/-) mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis. Conclusion: Spontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1(d/-) mice. (C) 2021 The Author(s). Published by Elsevier Inc

Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach

Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach

Distinct roles for REV-ERBα and REV-ERBβ in oxidative capacity and mitochondrial biogenesis in skeletal muscle.

The nuclear receptors REV-ERBα and REV-ERBβ have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERBβ is thought to be redundant to REV-ERBα. Recent work has highlighted REV-ERBα's role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERBβ-deficiency presented with a similar skeletal muscle phenotype as REV-ERBα-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERBβ drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERBβ in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid β-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERBβ-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid β-oxidation. Consistent with these results, REV-ERBβ-deficient mice exhibited an altered metabolic phenotype compared to wild-type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERBβ may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERBβ in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERBα versus REV-ERBβ selective ligands may have therapeutic utility in the treatment of metabolic syndrome

Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour

Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBα and β, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour. These data are consistent with increased anxiety-like behaviour of REV-ERBβ-null mice, in which REV-ERB agonists have no effect. These results indicate that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety

REV-ERBβ-deficient mice exhibit an altered metabolic phenotype and feeding schedule.

<p><b>(A)</b> Real-time respiratory exchange ratio (RER) monitoring of pre-acclimated male WT (black square) versus REV-ERBβ KO mice (gray circles) using indirect calorimetry. Mice were fed normal chow over a 3 day period. (F(380,4568) = 5.475, p<0.0001). <b>(B)</b> Average RER value, <b>(C)</b> energy expenditure, and <b>(D)</b> infrared activity beam break counts, indicating movement, for day versus night of the mice in panel A. (n = 7 per group). <b>(E)</b> Food intake measurements of male WT (black square) versus male REV-ERBβ KO mice (gray circles) fed normal chow over a 2 day period. <b>(F)</b> Average fasting RER value taken from a 6 hour period during the fast. (n = 7 per group) Data are representative of 2 independent experiments demonstrating similar results. Experiments using female mice demonstrated similar results (data not shown). Values are mean±s.e.m. Average RER was obtained using ANCOVA (analysis of covariance)[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196787#pone.0196787.ref038" target="_blank">38</a>] with ambulatory activity used as a covariate. Statistical significance was assessed using two-way ANOVA or Student’s two-tailed <i>t-</i>tests. <i>* p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.005.</p

Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype

International audienceAbstractBackgroundFunctional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target.Methods and resultsMolecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28.ConclusionsOur studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes

REV-ERBβ-deficient mice exhibit an altered metabolic phenotype and feeding schedule.

<p><b>(A)</b> Real-time respiratory exchange ratio (RER) monitoring of pre-acclimated male WT (black square) versus REV-ERBβ KO mice (gray circles) using indirect calorimetry. Mice were fed normal chow over a 3 day period. (F(380,4568) = 5.475, p<0.0001). <b>(B)</b> Average RER value, <b>(C)</b> energy expenditure, and <b>(D)</b> infrared activity beam break counts, indicating movement, for day versus night of the mice in panel A. (n = 7 per group). <b>(E)</b> Food intake measurements of male WT (black square) versus male REV-ERBβ KO mice (gray circles) fed normal chow over a 2 day period. <b>(F)</b> Average fasting RER value taken from a 6 hour period during the fast. (n = 7 per group) Data are representative of 2 independent experiments demonstrating similar results. Experiments using female mice demonstrated similar results (data not shown). Values are mean±s.e.m. Average RER was obtained using ANCOVA (analysis of covariance)[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196787#pone.0196787.ref038" target="_blank">38</a>] with ambulatory activity used as a covariate. Statistical significance was assessed using two-way ANOVA or Student’s two-tailed <i>t-</i>tests. <i>* p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.005.</p