Resistance to diet-induced adiposity in cannabinoid receptor-1 deficient mice is not due to impaired adipocyte function

Abstract

BackgroundOveractivity and/or dysregulation of the endocannabinoid system (ECS) contribute to development of obesity. In vitro studies indicate a regulatory role for the cannabinoid receptor 1 (CB1) in adipocyte function and CB1-receptor deficient (CB1-/-) mice are resistant to high fat diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown.MethodsWe evaluated adipose tissue differentiation/proliferation markers and quantified lipogenic and lipolytic activities in fat tissues of CB1-/- and CB1+/+ mice fed a high-fat (HF) or a high-fat/fish oil (HF/FO) diet as compared to animals receiving a low-fat chow diet. Comparison between HF diet and HF/FO diet allowed to investigate the influence of dietary fat quality on adipose tissue biology in relation to CB1 functioning.ResultsThe adiposity-resistant phenotype of the CB1-/- mice was characterized by reduced fat mass and adipocyte size in HF and HF/FO-fed CB1-/- mice in parallel to a significant increase in energy expenditure as compared to CB1+/+ mice. The expression levels of adipocyte differentiation and proliferation markers were however maintained in these animals. Consistent with unaltered lipogenic gene expression, the fatty acid synthesis rates in adipose tissues from CB1-/- and CB1+/+ mice were unchanged. Whole-body and adipose-specific lipoprotein lipase (LPL) activities were also not altered in CB1-/- mice.ConclusionsThese findings indicate that protection against diet-induced adiposity in CB1-deficient mice is not related to changes in adipocyte function per se, but rather results from increased energy dissipation by oxidative and non-oxidative pathways.

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

“…We demonstrate slowed glucose clearance in young CB 1 R −/− mice, which is corroborated by recent data (9). Our mechanistic analysis suggests that this profile rather reflects the decreased glucose need of peripheral tissues than any metabolic impairment because (i) both fasting (baseline) and terminal glucose levels are unchanged, (ii) CB 1 R −/− mice exhibit reduced muscle and adipose tissue mass (8), (iii) CB 1 R −/− mice respond properly to insulin challenge, and (iv) in islets isolated from CB 1 R −/− mice when islet dissection precludes the influence of tissue-derived or environmental confounds on glucose utilization, an improved relationship of insulin and glucagon secretion was observed. Likewise, we found improved insulin vs. glucagon secretion from morphologically similar pancreatic islets isolated from mice subjected to ω3-PUFA enrichment during fetal development.…”

“…eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2)(3)(4)(5)(6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4,(7)(8)(9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.…”

“…eCB signaling has been linked to the molecular control of insulin and glucagon release (2)(3)(4). Considering that both CB 1 R −/− and MAGL −/− mice are lean (7,8), we suggest that their mixed pancreatic islets allow for improved short-range insulin signaling between α and β cells ("histoarchitectural gain of function"), which can serve as a feedback mechanism increasing the ratio of insulin to glucagon secretion under high glucose availability. This hypothesis is also supported by genetic data upon conditional insulin receptor knockout in α cells (56), which induces hyperglucagonemia and glucose intolerance.…”

“…Our knockout analysis focused on adult animals because both CB 1 R −/− and MAGL −/− mice are lean (7,8,52) and resistant to high-fat diet-induced obesity or diabetes (4,(7)(8)(9). Although unchanged basal blood glucose and insulin levels of CB 1 R −/− and MAGL −/− mice were reported under standard feeding conditions (7,52), glucagon regulation-and particularly insulin/glucagon balance-in these mice remain unknown.…”

Hemp Seed Oil Inhibits the Adipogenicity of the Differentiation-Induced Human Mesenchymal Stem Cells through Suppressing the Cannabinoid Type 1 (CB1)

“…This could be attributed to the fact that the acid form of THC (THCA) creates fewer and smaller lipid droplets than rosiglitazone in hMSCs [13,14] and, as previously stated, that most of the CBD and THC were appropriately stored in hemp seed oil in the form of acidic precursor [15,16]. Furthermore, as PPAR-γ and CEBP-α are two master transcription factors that govern the differentiation and proliferation of adipocytes [17], we confirmed that the…”