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Genetics Of Obesity

Genetics Of Obesity

The severity of obesity has increased widely over past few decades, leading to enormous hardship on human health. Besides cosmetic concern obesity is a complex disease which is associated with premature mortality (death rate) and is a serious public health. Obesity is a major risk factor for cardiovascular diseases, pulmonary diseases (such as sleep apnoea), metabolic diseases (e.g. diabetes and dyslipidemia), osteoarticular diseases, for several of the commonest forms of cancer and for serious psychiatric illness. In recent years the impact of obesity was seen on communicable diseases like viral infection, during COVID pandemic the individuals with obesity were at higher risk of hospitalization and severe illness. The World Obesity Atlas 2022, published by the World Obesity Federation, predicts that one billion people globally, including 1 in 5 women and 1 in 7 men, will be living with obesity by 2030. Non -communicable diseases (NCD) Risk Factor Collaboration said in 2016 almost 2 billion adult were overweighed & by 2025 about 20% of world population will have obesity.

Obesity is widely characterized in two broad categories:

  • Monogenic obesity
  • Polygenic obesity

Monogenic obesity is very rare and severe, it is inherited in mendelian pattern i.e. involves small or large chromosomal deletion or single gene defect, while polygenic obesity is common obesity that follows a pattern of heredity and is found in many individual, results due to hundreds of polymorphism, each having a small effect.

Basically, there is a strong genetic component responsible for large interindividual variation in body weight that determines people’s response to this ‘obesogenic environment’. The central nervous system (CNS) and neuronal pathways that control the hedonic aspects of food intake have emerged as the major source of body weight for both monogenic and polygenic obesity.

In 1950, recessive mutant colony in house mice lack homozygous recessive ob gene & suffered with hyperphagia. It involve decreased energy expenditure & early onset of obesity. In 1958, Hervey & Hausberger experiment confirmed the presence of this factor in mice. They perform Reverse Genetics on ob gene which encode leptin, they show ob/ob recessive mouse suffered from severe obesity due to leptin deficiency caused by mutation in ob gene. In 1994, Jeffery Friedman discovered the Fat-Melting Adipocyte Hormone Leptin in humans; which is a product of obese (ob) gene. Its discovery has provided the missing link in the regulation of body weight and energy balance and it also added an extra impetus to research in obesity. Now leptin gene became the candidate gene for human obesity.

The Genetic Investigation of Anthropometric Traits (GIANT) is a large scale Collaboration that seeks to identify genetic loci that modulate human body on basis of size, shape, height & measures of obesity. More than 80 genome wide linkage studies have been identified & more than 300 chromosomal locci are there with evidence of linkage with obesity trait in human.

One of the most widely used modifications in the development of targeted therapeutic agents in the brain is the addition of hydrophilic polyethylene glycol (PEG)-containing polymers. However, PEG-modified leptin is unable to pass through the Blood Brain Barier and thereby reduce body weight in humans. So strategies that improve the passage of leptin to the brain include the development of modifications in the structure of leptin or leptin analogues as well as the development of new leptin receptor agonists with increased BBB permeability. Beside Leptin theory, fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. This is a gene therapy method which is being studied at a global level. The study of leptin with the help of mice model helps us to understand the leptin receptor and the underlying intracellular signaling pathway which is specifically activated in the corresponding parts of the brain, irrespective of mechanism responsible for leptin resistance. So obesogenic environment can be used to cure monogenic obesity.

M.Sc. Biotechnology First Year
School of Biosciences