Leptin gene mutation and its implications on obesity: overview, presentation, and treatment
Cassie Keinath
Student, Central Michigan University
3 December 2018
Abstract:
1. Introduction
The leptin gene codes for the protein leptin, which is an 167 amino-acid long protein chain. Leptin was originally discovered in ob/ob mice, which are animal models that have a mutation in the leptin (LEP) gene. This is caused by the homozygous mutation in the leptin gene, leading to no circulating leptin in the animal’s body. Due to this mutation, these mice tend to display extreme hyperphagia and are very obese [1]. Since the discovery of this mutation in the leptin gene in mice, less than two dozen humans with the mutation since 1997 have been identified [1]. Humans with this mutation tend to have a very distinct clinical presentation. While most humans with obesity often struggle to combat the disease with diet, exercise, weight loss, pharmaceuticals and bariatric surgery, obesity due to leptin deficiency has a treatment option that has shown to be successful in helping the patients lose and manage their weight [2]. While this mutation is rare, studying mice and humans with congenital leptin deficiency has led to the discovery of specific uses for leptin.
2. History of the Mutation
Mutation in the LEP gene was first discovered in mice, but it has also been seen humans. The first two humans with this mutation were identified in 1997. The two patients were cousins who both showed extreme obesity that they developed very early on in their lives [leptin and leptin receptor related monogenic obesity]. It was noted that there was multiple consanguineous relationships in this family, which would lead to a prevalence of a phenotype of a autosomal recessive allele. The first mutation identified was a frameshift mutation, which led to a shorten protein. This mutation causes failed protein secretion so these two patient had undetectable levels of circulating leptin in their bodies [leptin and leptin receptor related monogenic obesity]. Since these first two cousins with LEP gene mutation were identified, six other individuals from five families have been identified that carry this same mutation [leptin and leptin receptor related monogenic obesity]. In addition to this mutation in the gene, one family showed five individuals with a missense mutation in the LEP gene that also led to undetectable levels of leptin in the body. An individual with a substitution mutation, and someone with a new homozygous mutation in the LEP gene have been identified [leptin and leptin receptor related monogenic obesity].
3. Leptin’s Physiological Roles
Through studying humans with the LEP gene mutation, researchers have been able to identify specific functions that leptin plays in the body. Many of these functions are important for regulating energy expenditure and caloric intake. Leptin also plays a role in the neuroendocrine function of the body, as well as regulating metabolism and certain signaling pathways [Narrative Review: The Role of Leptin in Human Physiology: Emerging Clinical Applications].
3.1 Leptin’s Role in Energy Homeostasis
Leptin plays a significant role in regulating how to body takes in and uses its energy [narrative]. Since leptin is normally secreted from fat cells, leptin is a way to tell the body how much energy is in storage. Leptin directs the central nervous system (CNS) to adjust its energy expenditure and food intake, thus being a main source of appetite regulation for the body [N]. If leptin levels are low, that signals to the brain that energy reserves are low and the body needs to take in more energy, thus resulting in an increase in food intake. When leptin binds to its receptors in the hypothalamus, a pathway is activated the controls anorexigenic and orexigenic neuropeptides. These neuropeptides both diminish and stimulate appetite in the body, respectively [N]. In addition to leptin’s role in regulating appetite, it also acts on the mesolimbic dopamine system, which is involved in the brains reward and motivation for eating [N].