Objective

The high lipolytic and metabolic capacity of brown adipose tissue (BAT) makes it a promising therapeutic strategy for metabolic disorders such as type 2 diabetes and obesity. Traditional approaches to inducing BAT have focused either on ex vivo expansion and transplantation as a cell therapy; endogenous induction using adrenergic agonists; or extended periods of cold exposure. Whilst all of these are viable, each has its own set of associated disadvantages. To this end, we have used BAT derived from adipose-derived stem cells (ADSC’s) in cell-based screening to discover novel natural extracts derived from edible parts of plants that might serve as a safer means of both expanding BAT or brown-like adipose depots in white adipose tissue and subsequently inducing brown-like adipocytes to increase their energy expenditure capability.

To achieve this aim, Plasticell first used Combicult®, a proprietary, bead-based combinatorial cell culture technology to discover a novel protocol able to differentiate ADSC’s into human BAT. The human BAT was induced by known adrenergic agonists, exhibited a gene expression profile consistent with that previously published elsewhere and displayed higher metabolic activity when analysed using Agilent’s Seahorse XF Analyzer.

In collaboration with Pierre Fabre Laboratories, Plasticell used cell-based phenotypic screening to screen the in-vitro derived BAT against a library of natural extracts obtained from edible parts of plants. Primary hits were identified using an immunoassay against UCP1, the thermogenic protein uniquely expressed on the mitochondrial membrane of brown and brown-like adipose tissue. Secondary validation was performed using Agilent’s MitoXpress oxygen consumption assay. Validated hits from the screen increased oxygen consumption rate in the Combicult®-derived human BAT.

A second screen was then performed to find natural extracts capable of trans-differentiating white adipose tissue (relatively abundant in adult humans) into brown-like adipocytes, which are relatively rare in adult humans. Using the same screening approach as before, a number of validated hits induced brown-like adipocytes with a higher basal metabolic activity upon measurement using the MitoXpress oxygen consumption assay.

In conclusion, Plasticell has discovered a number of novel natural extracts able to convert human white fat to brown-like adipocytes as well as extracts able to induce higher metabolic activity in BAT. Plasticell utilised Agilent’s XF instruments as well as soluble metabolic assays in an end-to-end fashion to both establish metabolic capacity of the target cells for the screen as well as validate hits from the resulting screens.