A Study Using Human Abdominal Adipose Tissue Biopsies to Characterize the Role of Endocannabinoids in Adipocyte Differentiation

Condition(s) studied

Investigational drug(s) / intervention(s)

Collection of adipose tissue samples: Collection of small-volume adipose tissue samples (a few cubic centimeters) during a previously scheduled abdominal surgery.

Study summary

Abdominal obesity and type 2 diabetes are associated with hyperactivation of the endocannabinoid system. Several animal and human studies indicate that circulating endocannabinoid levels correlate with body fat mass. Thus, adipose tissue, which possesses the enzymatic machinery of the endocannabinoid system, may be the primary producer of plasma endocannabinoids.

Today, it is well established that stimulation of the endocannabinoid system, through the activation of cannabinoid receptor 1 (CB1R) located in the brain, leads to increased food intake and weight gain. Furthermore, peripheral CB1R present in adipose tissue are also directly involved in energy storage processes. Indeed, activation of the endocannabinoid system in adipose tissue is associated with stimulation of pathways leading to the uptake of carbohydrates and fatty acids, as well as their storage in the form of triglycerides.

Adipose tissue consists primarily of mature adipocytes, and activation of the endocannabinoid system appears to play a key role in increasing fat mass by promoting the hypertrophy of these adipocytes through the stimulation of lipogenesis. However, the vascular stromal fraction also contains stem cells capable of generating new adipocytes, and an autocrine action of endocannabinoids on progenitor cells could also contribute to its expansion by promoting hyperplasia.

That is why, in this project, the investigators aim to study the impact of endocannabinoids on the differentiation of stem cells from the stromal-vascular fraction into adipocytes. In particular, the investigators will seek to compare the impact of endocannabinoids on the differentiation capacity of stem cells derived from adipose tissue collected from patients with obesity, with or without diabetes, compared to controls.

These data, combined with those obtained in parallel in mice, could help determine whether adipose tissue (visceral and/or subcutaneous) is a priority target for the development of CB1R-blocking molecules (such as rimonabant) with exclusively peripheral action (which do not cross the blood-brain barrier to avoid psychiatric side effects) for the treatment of metabolic obesity and type 2 diabetes.

Eligibility

Primary outcome measure(s)

• Monitoring the differentiation of stem cells from the stromal-vascular fraction into adipocytes — At baseline, biopsies of visceral and subcutaneous adipose tissue will be performed in the operating room during patients' visceral surgery. The samples will be promptly transferred to the INSERM laboratory for stem cell culture to assess adipocyte diffe
  * Stem cell population in the stromal-vascular fraction prior to culture * Monitoring of stem cell differentiation into adipocytes in the presence of a CB1 receptor agonist, antagonist, or solvent (Oil Red O staining, mRNA markers, flow cytometry) * Kinetics of endocannabinoid release by cells during differentiation, assessed by RT-PCR of mRNAs. Quantification will be performed by liquid chromatography coupled with mass spectrometry (LC-MS).

Trial sites (1)

More Centre Hospitalier Universitaire Dijon trials in France