The neuronal control of metabolism has been extensively studied during the past 30 years and extensive observations in humans and animal models have highlighted that the hypothalamus is the primary brain area that regulate energy balance. Neuronal populations in the hypothalamus form neurocircuits that modulate appetite, energy expenditure and systemic metabolism. These hypothalamic neurocircuits form direct axonal connections with areas of the brainstem, which coordinate the metabolic responses of peripheral organs like the liver, pancreas, and adipose tissues, through the modulation of the autonomic nervous system. Genetic and environmental factors can cause the dysregulation of these hypothalamic neurocircuits, altering energy balance and facilitating weight gain, obesity and CMDs. Understanding the underpinning causes of the dysregulation of hypothalamic neurocircuits is crucial for developing effective treatments to regain effective energy balance.
Several studies have shown how alterations of the nutritional levels during pregnancy or early postnatal period affect the development of axonal connections in hypothalamic neurocircuits in mice, which can lead to maladaptive maturation, promoting early dysregulation and the onset of overweight at an early age. In rodents and humans, being overweight at an early age is an indicator of the onset of childhood obesity. Children and adolescents with overweight or obesity present higher risk of becoming young adults with obesity and developing other CMDs at an early age, threatening their healthy growth and development. Although lifestyle change programs promoting healthy eating and physical exercise are beginning to reduce the incidence of overweight and obesity in children, it is essential to investigate the underlying causes and environmental factors that promote the dysregulation of metabolic neurocircuits at an early age.
At the Metabolic Neurocircuits Laboratory, we investigate the development and function of hypothalamic neurocircuits with the following objectives:
- Investigating the formation and maturation of hypothalamic axonal connections to the hindbrain and their subsequent adult function in the regulation of metabolism.
- Delineating the metabolic roles of specific neuronal subpopulations located at the paraventricular area of the hypothalamus (PVH)
- Identify hypothalamic neuronal populations that are sensitive or resilient to the impact of high-fat diets as potential therapeutic targets.
To this end, we use animal experimentation models (transgenic mice to identify neuronal populations) in combination with:
- advanced neuroscience techniques (chemogenetics, AAVs, circuit mapping, brain clearing, in situ RNA, etc.)
- sequencing (bulk and single-cell RNAseq)
- molecular biology techniques (RT-PCR, western blot, etc.)
- metabolic phenotyping protocols (metabolic cages, indirect calorimetry, ITT, GTT, high-fat diets, etc.)
- “maternal programming” interventions using high-fat diets at different stages of development.