Metabolic Impact Of Moderate Leptin And Insulin Reduction

Objective:Leptin,a hormone produced by the fat cells and secreted into circulation,sends signals to the hypothalamus in the brain to reduce food intake and increase energy expenditure.Insulin is synthesized by β cells of pancreatic islets,which play a central role in regulating glucose levels in the body.These two hormones ate regarded as the main anabolic hormone in the body.Leptin deficiency,like ob/ob mice,can clearly developed manifest obesity.And lack of insulin production is the primary cause of type1 diabetes and some type 2 diabetes in later stages.It was later found that most obese individuals are not leptin deficient but are instead leptin resistance with high levels of circulating leptin.Insulin resistance,a hallmark of type 2 diabetes,occurs when insulin reduces the ability to force cells to absorb blood glucose for energy.Leptin and insulin resistance are the pathophysiologic factor of obesity and type 2 diabetes.Hormone resistance is often accompanied by elevated hormone levels.Classical cognition believes that hyperleptinemia and hyperinsulinemia are compensatory responses of leptin resistance and insulin resistance.However,studies have found that the rise of leptin and insulin often precedes the appearance of hormone resistance;Clinical application of leptin is not effective in treating obesity;and some drugs that reduce the level of leptin and insulin have a great effect on improving glucose and lipid metabolism.Therefore,in order to explore the causal relationship between hyperleptinemia,hyperinsulinemia and leptin and insulin resistance,we use a variety of mouse models with an increase or decrease circulating leptin and insulin levels to observe the changes of the sensitivity and total potency of leptin and insulin.It points to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.Methods:We used a variety of mouse models,(1)Inducible leptin overexpression mice:adipocyte-specific leptin transgenic mice.(2)Congenital partial leptin deficiency mice:one is the classic whole-body heterozygous leptin knockout mouse(OBHZ);the other is the fat cell-specific heterozygous leptin knockout mouse.(3)Inducible leptin deficiency mice: one is an adipocyte-specific inducible hybrid leptin knockout mouse;the other is an inducer dose-dependent adipocyte-specific leptin knockout mouse(4)Mice with mild inhibition of insulin secretion: pancreatic β-cell doxycycline dosedependent inducible Kir6.2(V59M)transgenic mice.A variety of mouse models can be used to regulate the amount of leptin and insulin in mice by genetic manipulation.To understand the effects of leptin and insulin,body weight,food intake,glucose tolerance and insulin tolerance were tested.Fat and liver tissue immunohistochemistry allowed insights into adipose tissue inflammation and hepatic triglyceride content.RT-q PCR gene level detection is helpful for the quantitative analysis of inflammation,fibrosis and liver steatosis.Results and Conclusions:(1)Increasing leptin levels in obese mice enhances body weight gain and aggravates glucose and lipid metabolism disorders.(2)Partial leptin deficiency on chow diet slightly increases body weight gain and do not show any functional differences in adipose tissue and liver.(3)Partially leptin-deficient mice on high-fat diet display improved glucose tolerance and insulin sensitivity.,reduced adipose tissue inflammation and alleviated fatty liver and liver fibrosis.(4)Partial leptin deficiency in obese mice reverses leptin resistance.(5)Partial insulin deficient mice are resistant to diet induced steatohepatitis.(6)Partial insulin reduction in obese mice helps maintain insulin sensitivity and protect mice from obesity and fatty liver during high-fat diet.