At the pinnacle of metabolic health: high altitude and fat burning

About the Project

Obesity (excessive body fat) is very common, and the number of obese/overweight people continues to rise globally. Obesity causes high blood sugar (diabetes) and high blood lipids that can lead to liver and heart disease. Medicines that reduce our appetite to cause weight loss work for some individuals, but  can be ineffective or cause harmful side effects in others. A complementary approach is to develop medicines or health interventions that reduce body fat accumulation through direct effects in the fat tissue itself.

Intriguingly, exposure to high altitude (HA) leads to weight loss and improved metabolic health due to a combination of oxygen deprivation (hypoxia) and cold exposure. The mechanisms underlying these protective effects, and whether they are sustained upon return to sea-level, is unknown. We recently showed that the oxygen sensing protein networks present within cells are directly involved in the process of new fat cell formation (PMID: 39209825; PMID: 33849008; PMID: 25377876). Even a short exposure to hypoxia, mimicking depleted oxygen levels at the summit of Mt Kilimanjaro (~5800m), led to weight and fat mass loss. Intriguingly, return to sea level selectively increased the capacity of a specialised type of fat tissue called “brown” fat that burns calories from their stored lipid to generate heat.

We hypothesise that directly targeting the oxygen-sensing pathway in fat cells offers an alternative therapeutic strategy to counteract the adverse metabolic consequences of obesity.

The PhD candidate will test this hypothesis through the following objectives:

1. Characterise the mechanisms whereby hypoxia alone, or combined hypoxia and cold exposure beneficially and sustainably programmes fat cell metabolism.
2. Determine the mechanisms whereby hypoxia alone or combined hypoxia and cold exposure re-programme fat cell progenitor fate towards beneficial mature fat cell phenotypes.
3. Develop a human fat-on-a-Chip model to mimic conditions of hypoxia/cold to determine conservation of translationally relevant protein targets with therapeutic potential.

This project aims to understand the integrative nature of high-altitude effects on adipose tissue formation and function and whether the mechanisms underpinning this effect can be harnessed towards novel anti-obesity strategies.

Training: The student will receive state-of-the-art training in metabolic physiology using  high-resolution indirect calorimetry (Sable Promethion Core system) body composition analyses (time-domain)TD-NMR, hypoxia chamber manipulation, adipose tissue single nuclei RNA-sequencing and cutting edge molecular biology techniques (nanostring GeoMX spatial transcriptomics, western blotting, CRISPR gene editing). Key training in cell biology will cover cellular energetics (Seahorse technology), Cytek spectral flow cytometry, on-chip human fat modelling (emulate system) will be complemented with organ imaging (Miltenyi Blaze 3D-lightsheet microscope).

Entry qualifications

We seek a highly motivated individual dedicated to in vivo modelling and wet-lab based research in adipose tissue metabolism in the context of metabolic disease. The applicant must have a Masters in a relevant subject area (biomedical sciences, physiology, immunology, metabolic medicine, pharmacology) and an aptitude for experimental design, execution and data generation/analysis to publication standard. Experience in flow cytometry, cell culture and molecular skills will be advantageous.