The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that "program" obesity from conception.

Understanding the developmental origins of health and disease is integral to overcome the global tide of obesity and its metabolic consequences, including atherosclerotic cardiovascular disease, type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease. The rising prevalence of obesity has been attributed, in part, to environmental factors including the globalization of the western diet and unhealthy lifestyle choices. In this review we argue that how and when such exposures come into play from conception significantly impact overall risk of obesity and later health outcomes. While the laws of thermodynamics dictate that obesity is caused by an imbalance between caloric intake and energy expenditure, the drivers of each of these may be laid down before the manifestation of the phenotype. We present evidence over the last half-century that suggests that the temporospatial evolution of obesity from intrauterine life and beyond is, in part, due to the conditioning of physiological processes at critical developmental periods that results in maladaptive responses to obesogenic exposures later in life. We begin the review by introducing studies that describe an association between perinatal factors and later risk of obesity. After a brief discussion of the pathogenesis of obesity, including the systemic regulation of appetite, adiposity, and basal metabolic rate, we delve into the mechanics of how intrauterine, postnatal and early childhood metabolic environments may contribute to adult obesity risk through the process of metabolic conditioning. Finally, we detail the specific epigenetic pathways identified both in preclinical and clinical studies that synergistically "program" obesity.

Therapeutic silencing of FSP27 reduces the progression of atherosclerosis in Ldlr-/- mice.

BACKGROUND AND AIMS: Obesity, hepatosteatosis, and hypertriglyceridemia are components of the metabolic syndrome and independent risk factors for cardiovascular disease. The lipid droplet-associated protein CIDEC (cell death-inducing DFFA-like effector C), known in mice as FSP27 (fat-specific protein 27), plays a key role in maintaining triacylglyceride (TAG) homeostasis in adipose tissue and liver, and controls circulating TAG levels in mice. Importantly, mutations and SNPs in CIDEC are associated with dyslipidemia and altered metabolic function in humans. Here we tested whether systemic silencing of Fsp27 using antisense oligonucleotides (ASOs) was atheroprotective in LDL receptor knock-out (Ldlr-/-) mice. METHODS: Atheroprone Ldlr-/- mice were fed a high-fat, high-cholesterol diet for 12 weeks while simultaneously dosed with saline, ASO-ctrl, or ASO-Fsp27. RESULTS: Data show that, compared to control treatments, silencing Fsp27 significantly reduced body weight gain and visceral adiposity, prevented diet-induced hypertriglyceridemia, and reduced atherosclerotic lesion size both in en face aortas and in the aortic root. CONCLUSIONS: Our findings suggest that therapeutic silencing of Fsp27 with ASOs may be beneficial in the prevention and management of atherogenic disease in patients with metabolic syndrome.

Amelioration of diet-induced steatohepatitis in mice following combined therapy with ASO-Fsp27 and fenofibrate.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD progresses from benign steatosis to steatohepatitis (NASH) to cirrhosis and is linked to hepatocellular carcinoma. No targeted treatment is currently approved for NAFLD/NASH. We previously showed that fat-specific protein 27 (FSP27), a lipid droplet-associated protein that controls triglyceride turnover in the hepatocyte, is required for fasting- and diet-induced triglyceride accumulation in the liver. However, silencing Fsp27 with antisense oligonucleotides (ASOs) did not improve hepatosteatosis in genetic nor nutritional mouse models of obesity. Herein, we tested the therapeutic potential of ASO-Fsp27 when used in combination with the PPARα agonist fenofibrate. C57BL/6 mice were fed a high-trans-fat, high-cholesterol, high-fructose diet for eight weeks to establish NASH, then kept on diet for six additional weeks while dosed with ASOs and fenofibrate, alone or in combination. Data show that ASO-Fsp27 and fenofibrate synergize to promote resistance to diet-induced obesity and hypertriglyceridemia and to reverse hepatic steatosis, inflammation, oxidative stress, and fibrosis. This multifactorial improvement of liver disease noted when combining both drugs suggests that a course of treatment that includes both reduced FSP27 activity and activation of PPARα could provide therapeutic benefit to patients with NAFLD/NASH.

Characterization of a cold-adapted DNA photolyase from C. psychrerythraea 34H.

The phrB gene encoding a putative cold-adapted DNA photolyase was cloned from the bacterial genomic DNA of Colwellia psychrerythraea 34H, a psychrophilic bacterium. Recombinant DNA photolyase, rCpPL, was overexpressed and purified from three different vectors. rCpPL binds its DNA substrate by flipping a cyclobutane pyrimidine dimer (CPD) into its active site and repairs CPD-containing DNA in vitro. rCpPL contains one catalytic flavin adenine dinucleotide (FAD) cofactor, but displays promiscuity in cofactor binding, in which either a flavin mononucleotide (FMN) or a methenyltetrahydrofolate (MTHF) molecule is bound as an antenna molecule and found in sub-stoichiometric amounts. The UV/Vis spectrum of oxidized rCpPL shows that the FADOX absorption maximum is the most red-shifted reported for a PL, suggesting a unique cavity electrostatic environment. Modest FAD vibronic structure suggests that the binding pocket is more flexible than warmer PLs, corroborating the hypothesis that psychrophilic proteins must be highly flexible to function at low temperatures. Fluorescence excitation data show that the freshly purified flavin cofactor is in its fully reduced state (FADH¯). A homology analysis of PL protein structures spanning 70 °C in growth temperature supports the data that the structure of CpPL is quite different from its warmer cousins.

Therapeutic silencing of fat-specific protein 27 improves glycemic control in mouse models of obesity and insulin resistance.

Obesity is a component of the metabolic syndrome, mechanistically linked to diabetes, fatty liver disease, and cardiovascular disease. Proteins that regulate the metabolic fate of intracellular lipid droplets are potential therapeutic candidates to treat obesity and its related consequences. CIDEC (cell death-inducing DFFA-like effector C), also known in mice as Fsp27 (fat-specific protein 27), is a lipid droplet-associated protein that prevents lipid mobilization and promotes intracellular lipid storage. The consequences of complete loss of FSP27 on hepatic metabolism and on insulin resistance are controversial, as both healthy and deleterious lipodystrophic phenotypes have been reported in Fsp27-/- mice. To test whether therapeutic silencing of Fsp27 might be useful to improve obesity, fatty liver, and glycemic control, we used antisense oligonucleotides (ASOs) in both nutritional (high-fat diet) and genetic (leptin-deficient ob/ob) mouse models of obesity, hyperglycemia, and hepatosteatosis. We show that partial silencing Fsp27 in either model results in the robust decrease in visceral fat, improved insulin sensitivity and whole-body glycemic control, and tissue-specific changes in transcripts controlling lipid oxidation and synthesis. These data suggest that partial reduction of FSP27 activity (e.g., using ASOs) might be exploited therapeutically in insulin-resistant obese or overweight patients.

Bitter melon reduces head and neck squamous cell carcinoma growth by targeting c-Met signaling.

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat, and despite of advances in treatment, the overall survival rate has only modestly improved over the past several years. Thus, there is an urgent need for additional therapeutic modalities. We hypothesized that treatment of HNSCC cells with a dietary product such as bitter melon extract (BME) modulates multiple signaling pathways and regresses HNSCC tumor growth in a preclinical model. We observed a reduced cell proliferation in HNSCC cell lines. The mechanistic studies reveal that treatment of BME in HNSCC cells inhibited c-Met signaling pathway. We also observed that BME treatment in HNSCC reduced phosphoStat3, c-myc and Mcl-1 expression, downstream signaling molecules of c-Met. Furthermore, BME treatment in HNSCC cells modulated the expression of key cell cycle progression molecules leading to halted cell growth. Finally, BME feeding in mice bearing HNSCC xenograft tumor resulted in an inhibition of tumor growth and c-Met expression. Together, our results suggested that BME treatment in HNSCC cells modulates multiple signaling pathways and may have therapeutic potential for treating HNSCC.