Developmental Role for Endocannabinoid Signaling in Regulating Glucose Metabolism and Growth

Abstract

Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnr1) antagonist reduces food intake, suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knockout ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced IGF-I levels without alterations of growth hormone (GH) levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist that had no effect on glucose metabolism, suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also showed similar leptin sensitivity as ob/ob mice, suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data also suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-I axis, and improve β-cell function and glucose homeostasis in the setting of leptin deficiency.

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

“…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. 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.…”

“…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.…”

“…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.…”

Cannabinoid receptor signaling regulates liver development and metabolism

“…EC signaling has previously been implicated in promoting trophoblast cell lineage differentiation (Sun et al, 2010) and neural development (Palazuelos et al, 2012;Psychoyos et al, 2012); one indication that Cnr signaling may also affect endodermal development and/or metabolic function was observed in Cnr1 −/− ob/ ob double-mutant mice, which exhibit growth retardation and exacerbated glucose intolerance (Li et al, 2013). The developmental phenotypes observed in Cnr mutant zebrafish support previously described liver abnormalities in Cnr knockout mice: the impact of Cnr activity on embryonic liver maturation might explain the delayed or aberrant hepatocyte proliferation and recovery of liver mass seen after partial hepatectomy in adult Cnr1 and Cnr2 knockout mice (Teixeira-Clerc et al, 2010), as the recapitulation of proliferation-promoting developmental pathways has been shown to be important during liver regeneration (Goessling et al, 2008;Nissim et al, 2014;Yin et al, 2012).…”

Adipokines and their Involvement as a Target of New Drugs

“…The correlation with hyper insulinemia and obesity, suggests that apelin may be anoth er However obesity itself, probably, is not the main determinant of increased plasma apelin, in fact circulating apelin concentration was not significantly correlated to BMI [99,100]. Other factors, such as inflammation and oxidative stress, could explain changes in plasma apelin observed in obesity [101,102]. Thus, increased apelin may be due to metabolic derangements that result from compensatory response to insulin resistance [101].…”