The role of clock dysfunction in obesity-related inflammation and insulin resistance

Obesity is now endemic across much of the world, and is set to become the biggest challenge to public health in the coming decades. While obesity can cause health problems as a consequence of biomechanical effects, the major threat is obesity-related metabolic disturbances, which drives insulin resistance and type-2 diabetes, dyslipidaemia, and cardiovascular disease.

It is now recognised that defective lipid (fat) storage in white adipose tissue (WAT) is directly linked to the severity of metabolic disturbance in obesity, and especially the development of insulin resistance and ultimately diabetes. However, it remains unclear what causes WAT dysfunction and how this leads to metabolic disease. We have recently identified a model in which obesity is not associated by elevated WAT inflammation (Hand et al 2014). Specifically, mice lacking the nuclear hormone receptor (NHR), Rev-erb, become profoundly obese even when maintained on a standard diet. This obesity is , and this obesity . However, in striking contrast to obese WT mice, the WAT in these knockout mice shows adipocyte hypertrophy with none of the expected influx of inflammatory cells, and importantly without loss of insulin sensitivity. We propose that loss of REV-ERBa permits enhanced adipocyte fat storage, without resulting in adipocyte cell stress, thus limiting inflammation, and loss of insulin sensitivity. Thus, the circadian clock is a key node linking metabolic and inflammatory responses in WAT, and may be central to obesity-related pathology in this tissue. The current proposal will determine the basis for this striking, and important phenotype.

Studies will characterize the impact of the clock on resident and infiltrating inflammatory cell profiles within the adipose tissue beds under normal and the obese state. This work will benefit from both global and tissue specific (e.g. adipo-CRExReverbflox; AdipoCRExBmal1flox) targeting of the clock, combined with local expertise in profiling inflammatory cell linage and activation state. Importantly, genetic and diatary manipulations will be accompanied by in vivo assessment of metabolic status, lipid handling and insulin/glucose homeostasis. To examine mechanisms through which the circadian clockwork within adipocytes and/or inflammatory cells (most notably macrophages) act to drive local tissue inflammation and insulin resistance, in vivo work will be complimented by cell and tissue culture, including co-culture models. Many of our transgenic lines carry clock driven luciferase reporters, allowing real-time assessment of circadian function both in vivo or in culture. Immune cell characterization will benefit from local expertise and substantial recent investment in single cell transcriptional profiling.

The multidisciplinary team draws on expertise from both FLS (Bechtold, Loudon) and FMHS (Ray). The candidate will be based in the lab of Dr. Bechtold, where they also receive intensive training in surgical approaches and whole animal physiological monitoring. The Bechtold lab has extensive experience with in vivo characterisation of circadian and metabolic pathways. Prof. Ray brings unique expertise in inflammation and clock biology, as well as molecular and genetic profiling and nuclear hormone receptor biology. Prof. Loudon brings extensive experience in circadian biology and the clock-immune interface, with expertise ranging from whole animal physiology to epigenetic programing.

Together, the multidisciplinary team and project provides an excellent training opportunity for the successful applicant. Owing to the high end in vivo training and cutting edge ex vivo cellular profiling, the candidate will be well positioned for a future research career in any aspect of life sciences. Our grouping are supported by multiple large externally funded grants, with many post-doctoral scientist, current PhD students and technical support - thereby providing a vibrant and supportive environment for the candidate.