Improving metabolic health by activation of futile adipose de novo lipogenesis

Obesity is a major metabolic disease manifested with increased peripheral and central accumulation of subcutaneous and visceral white adipose tissue (WAT). During prolonged cold exposure the subcutaneous WAT undergoes major morphological and functional alterations, leading to appearance of mitochondria-rich, UCP1-expressing beige adipocytes that promote energy dissipation and heat generation,  a process called fat browning. An under-appreciated function of WAT is its role in clearing glucose and amino-acid from plasma by converting them into lipids for storage. The synthesis of fatty acids from non-lipid precursors is called de novo lipogenesis (DNL). High fat diet or defective lipid metabolism often found in obese individuals suppresses DNL in the adipose tissue which renders the patients insulin resistant and diabetic. Against all expectations, it is becoming increasingly clear that activation of adipose DNL is beneficial for improved fat metabolism, glucose homeostasis, insulin sensitivity, and whole-body metabolism, especially when these pathways are active in visceral WAT. Most of the work to understand fat browning, has, however, been done in subcutaneous fat. Despite its critical importance in obesity-related metabolic disorders, the capacity of the visceral WAT to convert into beige-like adipose tissue, remains poorly investigated.

The Trajkovski group at the Unige recently made an unexpected discovery and showed that exposing microbiota-depleted mice to low temperatures promotes UCP1-independent browning of visceral WAT. This leads to a drastic metabolic activation of this tissue, and dramatic weight loss of the animals. Preliminary transcriptome analyses of the involved tissues show an unanticipated up-regulation of DNL and high glucose consumption specifically in visceral WAT. The gene expression data also indicate that under these conditions DNL might run in a futile cycle that is specific for the visceral WAT of microbiota-depleted cold-exposed mice. This raises the possibility that the visceral WAT is continuously degrading fat it has just synthesized; a situation which leads to a net loss of metabolic energy and might explain the drastic loss of fat mass in these animals.

The Klemm laboratory at UZH has recently discovered that adipocytes have specialized cellular machinery to control DNL in order to regulate healthy development of white adipocytes. The Klemm lab has established methods for the genetic perturbation of adipocytes by CRISPR-Cas9 gene knock outs and developed a set of approaches to trace incorporation of isotope labelled glucose and amino acids into fat to quantify DNL in these cells.

The central working hypothesis in our seed project is that futile DNL is the underlying reason for the drastic weight loss in the described mouse model.

To test this hypothesis we will carry out the following specific experiments, which will start the collaboration between UZH and UniGe:

  1. Use the isotope based tracing experiments to test if microbiota-depleted, cold exposed mice prepared at UniGe run futile visceral DNL.
  2. To identify factors involved in driving futile DNL we will analyze transcriptome changes in a differentiation time course of a CRISPR-Cas9 adipocyte K.O. model defective in futile DNL (already produced at UZH) and compare them to the transcriptome data obtained with the mouse model.

Participants

Dr. Robin Klemm, University of Zurich

Prof. Mirko Trajkovski, University of Geneva