IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin.

BACKGROUND: Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN: Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

Population Polymorphism of IFNL3 and IFNL4 Genes of Type 3 Interferon Associated with Spontaneous Clearance of Hepatitis C Virus in Representatives of Caucasian and Mongoloid Races.

The frequency of single nucleotide polymorphisms of IFNL3 gene (rsl12979860 and rs8099917) and dinucleotide polymorphism of IFNL4 gene (ss469415590) were estimated in healthy inhabitants of Mongolia and Irkutsk regions taking into account their races. Population and genetic studies were performed in 1520 conventionally healthy volunteers (blood donors), representatives of Caucasian and Mongoloid races. Significant race-related differences in the incidence of IFNL3 and IFNL4 gene polymorphisms associated with spontaneous clearance of hepatitis C virus were found in healthy volunteers.

[EPIDEMIOLOGIC MANIFESTATIONS OF VIRAL HEPATITIS C IN REPRESENTATIVES OF CAUCASIAN AND MONGOLOID RACES].

AIM: Present comparative epidemiologic characteristics of viral hepatitis C in Mongolia and Irkutsk Region taking into account racial origin of the studied populations. MATERIALS AND METHODS: The studies were carried out in 2009-014 on the territory of Irkutsk Region in Mongolia. Prevalence of viral hepatitis based on serological monitoring, virus RNA detection, risk factors, change in structure of circulating genotypes, hepatocellular carcinoma morbidity were studied. RESULTS: Epidemiologic manifestations of viral hepatitis C in Mongolia, in contrast to Irkutsk Region, are characterized by, a wider prevalence of the disease, predominance of the fraction of seropositive individuals in age category of above 50 years and predominance of genotype 1 virus in circulation. In recent years an evolution of diversity of circulating' irus genotypes, ook place towards a reduction of the fraction of genotype in Mongolia and Russia due tor ni ncrease of the fraction of genotype-3. Expressed,differences in average-annual values of hepatocellular carcinoma morbidity were detected, that were more than 10 times higher among Mongoloids compared with Caucasians. CONCLUSION: Pronounced differences were detected in manifestations of epidemic process of viral hepatitis C in Mongolia and Asian part of Russia, represented by Eastern Siberia, that are associated with ethnic, social and, cultural living conditions of the indigenous population.

Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats.

Hyperphagia triggers and accelerates diabetes, and prevents proper dietary control of glycemia. Inversely, the impact of hyperglycemia on hyperphagia and possible mechanistic cause common for these two metabolic disorders in type 2 diabetes are less defined. The present study examined the precise developmental process of hyperglycemia and hyperphagia and explored the alterations in the hypothalamic arcuate nucleus (ARC), the primary feeding and metabolic center, in Goto-Kakizaki (GK) rats with type 2 diabetes and nearly normal body weight. At mid 3 to 4 weeks of age, GK rats first exhibited hyperglycemia, and then hyperphagia and reduced mRNA expressions for anorexigenic pro-opiomelanocortin (POMC) and glucokinase in ARC. Furthermore, [Ca2+]i responses to high glucose in ARC POMC neurons were impaired in GK rats at 4 weeks. Treating GK rats from early 3 to mid 6 weeks of age with an anti-diabetic medicine miglitol not only suppressed hyperglycemia but ameliorated hyperphagia and restored POMC mRNA expression in ARC. These results suggest that the early hyperglycemia occurring in weaning period may lead to impaired glucose sensing and neuronal activity of POMC neurons, and thereby induce hyperphagia in GK rats. Correction of hyperglycemia in the early period may prevent and/or ameliorate the progression of hyperphagia in type 2 diabetes.