Crosstalk of central and peripheral circadian clocks in the regulation of adipose metabolic inflammation

Obesity and its secondary disorders like type-2 diabetes and the metabolic syndrome are a leading medical problem in modern society. The metabolic syndrome is characterized by altered glucose homeostasis and chronic low grade inflammation ("metaflammation"). A major risk factor for the development of overweight is the disruption of circadian rhythms. Circadian rhythm perturbations can occur due to trans-meridian travel, shift work or sleep impairments. A molecular circadian timing network coordinates daily physiological rhythms and is realigned or entrained to the daily 24-hour cycle by external cues such as the light-dark cycle. With the help of these inner clocks and their transcriptional output organisms anticipate recurring daily events by adapting physiological functions.

In mammals, the circadian network follows a hierarchical structure with a master clock located in the suprachiasmatic nuclei (SCN) of the ventral hypothalamus. The SCN clock is reset by the outer light-dark cycle and synchronizes central and peripheral clocks with external time.

Adipose tissue (AT) is both a metabolic and an endocrine organ and plays a major role in bodyweight regulation and energy metabolism. Besides adipocytes, AT also contains different immune cells – neutrophils and macrophages – which migrate through the tissue and play a role in the initiation of metaflammation. The migratory behavior of these cells is controlled by different chemoattractants, some of which are secreted in a circadian fashion from adipocytes themselves.

In this project I will elucidate the interplay between central and peripheral white adipose tissue clocks in the development of metabolic inflammation. I will further test the therapeutic potential of reinforcing peripheral adipose circadian rhythms for the prevention of metaflammation in an obesogenic environment.


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