Talk like a physiologist

Comorbidity — the existence of two or more related diseases

Leptin — a hormone produced by our body’s fat, regulating energy expenditure, heat production, appetite and sexual maturation

Metabolism — the body’s chemical process (happening in all our cells) of converting food into energy

Neural circuits — interconnected networks of neurons, the basic building blocks of the nervous system

Neuroendocrine — related to the release of hormones in the bloodstream

Physiological processes — the activities and functions that occur within living organisms to maintain life (e.g., metabolism, reproduction and digestion)

Puberty — the stage of development during which a person’s body undergoes physical and hormonal changes, leading to sexual maturity and the ability to reproduce

Reproductive health — the state of complete physical and mental well-being in all matters related to the reproductive system, including its functions and processes, throughout the life cycle

In the intricate symphony of our bodies, hormones take centre stage, regulating various physiological processes. These chemical substances act like messengers; after being made in one part of the body, they travel to other parts of the body where they help control how cells and organs perform their functions. Their influence can be of great significance, regulating everything from our metabolism to our reproductive health.

Among these remarkable molecules, leptin emerges as a key player, acting as a communicator between our body’s fat cells and vital organs. When the delicate balance of this hormonal communication is disrupted, such as in conditions like obesity, it can affect how our body handles both metabolism and reproductive health. Dr Carol Elias, a physiologist at the University of Michigan Medical School, is using a variety of molecular methods, such as genetics, to explore the neural basis of leptin action and its influence on metabolism and reproductive health.

A little bit about leptin

“Leptin is a hormone produced by our body’s fat, or white adipose tissue,” explains Carol. “It is secreted into the body’s blood circulation and reaches organs and tissues where receptors are located.” These receptors act as molecular ‘docking stations’, waiting for leptin’s arrival to relay crucial messages. Once leptin attaches to its receptors, it sends signals which lead to regulated responses in the body. These responses affect metabolism, appetite and reproductive health. “Leptin has many different roles related to energy expenditure, heat production, appetite and sexual maturation, among others,” explains Carol.

The diverse roles of leptin explain why its discovery was met with such enthusiasm. “The discovery of leptin in the 1990s was a significant moment for scientists in our field because it brought new possibilities to understand the cause and development of obesity, diabetes and diseases related to both, what we call ‘comorbidities’,” says Carol. “I was a neuroscience student at the University of São Paulo in Brazil at that time, and the excitement was huge because it turned out that the main site of leptin action is the brain.” This discovery marked a turning point in scientific exploration, revealing the neural circuits that control energy balance and reproductive functions.

How can we study leptin?

Investigating the function of leptin involves combining laboratory techniques and genetic manipulation. More specifically, Carol and her team employ genetically-modified mouse models (mice that have been altered at the genetic level) to reveal the complexities of leptin’s role.

These models can be created through two main approaches. The first method involves modifying a known or suspected disease-causing gene based on existing research findings. “If this gene is also found in mice, we can make modifications in this gene in the mouse and study the development of the disease and how we can treat it,” explains Carol. “The other method is the inverse path, i.e., we make changes in a gene we do not know the function of and investigate what this modification results in for the mouse.” If a disease occurs, this information is then used by other scientists to investigate whether a similar gene mutation is observed in humans with a comparable condition. Carol’s research focuses on factors associated with infertility, obesity and diabetes. By modifying specific genes, Carol and her team can observe the resulting physiological changes in the mice, offering valuable information about leptin’s function.

Brain mapping is a set of neuroscience techniques used to create a map of the brain’s structure and functions. This can involve identifying and understanding different regions of the brain and how they are connected, as well as determining the specific tasks or activities each region is responsible for. “To understand how the neurons are connected and how these connections generate a specific response related to hormone secretion or behaviour, we use what are called neuronal tracers,” says Carol. “These are molecules that enter the neurons and are transported through the axons (nerve fibres) to the terminals (where one neuron communicates with another via synapses).” By injecting neuronal tracers into specific areas of the brain and then examining their distribution using specialised tools, researchers can get important information about the brain’s intricate wiring. “Using this approach, we have learnt that many parts of the brain are connected in the metabolic control of reproduction,” explains Carol.

How does leptin connect energy to puberty and fertility?

“Our studies showed that leptin is one of the main hormones that signals energy availability to the brain,” says Carol. This communication plays a dual role: guiding the path of pubertal development and influencing the balance between energy storage, weight and fertility. “If not enough energy is available, the organism has a way to block reproduction,” explains Carol. “On the other hand, an excess of energy (i.e., obesity) may also decrease fertility because high levels of circulating hormones produced by the adipose tissue (e.g., leptin) may result in resistance, where cells fail to respond.” This highlights the intriguing link between metabolic health and reproductive health and emphasises the importance of hormonal balance for optimal fertility.

What has Carol’s team discovered?

Researching which parts of the brain connect metabolism and reproduction, Carol’s team has already discovered specific groups of neurons that can detect leptin and respond to control the neuroendocrine reproductive function.

Carol’s next steps include exploring the role of sex hormones, particularly testosterone, in the regulation of metabolism, and investigating the effect of childhood obesity in brain development and how it might shape the neuroendocrine response in adult life. These initiatives represent a frontier of discovery, set to reveal crucial insights into the complexity of hormonal regulation, metabolic pathways and reproductive functions.