Nutritional, hormonal, and depot-dependent regulation of the expression of the small GTPase Rab18 in rodent adipose tissue

Abstract

There is increasing evidence that proteins associated with lipid droplets (LDs) play a key role in the coordination of lipid storage and mobilization in adipocytes. The small GTPase, RAB18, has been recently identified as a novel component of the protein coat of LDs and proposed to play a role in both b-adrenergic stimulation of lipolysis and insulin-induced lipogenesis in 3T3-L1 adipocytes. In order to better understand the role of Rab18 in the regulation of lipid metabolism in adipocytes, we evaluated the effects of age, fat location, metabolic status, and hormonal milieu on Rab18 expression in rodent white adipose tissue (WAT). Rab18 mRNA was undetectable at postnatal day 15 (P15), but reached adult levels by P45, in both male and female rats. In adult rats, Rab18 immunolocalized around LDs, as well as within the cytoplasm of mature adipocytes. A weak Rab18 signal was also detected in the stromal-vascular fraction of WAT. In mice, fasting significantly increased, though with a distinct time-course pattern, Rab18 mRNA and protein levels in visceral and subcutaneous WAT. The expression of Rab18 was also increased in visceral and subcutaneous WAT of obese mice (diet-induced, ob/ob, and New Zealand obese mice) compared with lean controls. Rab18 expression in rats was unaltered by castration, adrenalectomy, or GH deficiency but was increased by hypophysectomy, as well as hypothyroidism. When viewed together, our results suggest the participation of Rab18 in the regulation of lipid processing in adipose tissue under both normal and pathological conditions.

Transgenic Adipose-specific Expression of the Nuclear Receptor RORα Drives a Striking Shift in Fat Distribution and Impairs Glycemic Control

“…Decreased expression of Rab GTPase-activating proteins has been reported to correlate with decreased glucose tolerance in an intraperitoneal GTT assay, aberrant glucose uptake and dysfunctional carbohydrate and energy homeostasis ( Hargett et al, 2016 , Chadt et al, 2015 ). Furthermore, we observed decreased Rab18 expression (that failed to attain significance, P = 0.06), which has been associated with impaired fat storage ( Pulido et al, 2011 ), and aberrant processing of lipids in adipose tissue ( Pulido et al, 2013 ) ( Fig. 5 F).…”

“…Furthermore, we identified decreased expression of Rab 18 and the Rab-GAPs, Tbc1d1 and AS160/Tbc1d4. This pattern of expression in adipose tissue has been associated with impaired glycemic control, energy homeostasis, and fat storage ( Hargett et al, 2016 , Chadt et al, 2015 , Pulido et al, 2013 ). The subcutaneous specific differential expression of several critical genes provided some insights into the subcutaneous lipodystrophic and glucose intolerant phenotype in the Tg-FABP4-RORα4.…”

Impaired Adipose Tissue Expandability and Lipogenic Capacities as Ones of the Main Causes of Metabolic Disorders

“…Moreover, obesity is associated with an increase in Rab18 expression, which suggests that upregulation of this GTPase may be an appropriate response to managing energy excess, an adaptive response to overcome the alterations in lipid metabolism occurring in obesity [ 55 ]. This participation in the regulation of lipid processing in adipose tissue takes place under both normal and pathological conditions [ 57 ].…”

Rab proteins implicated in lipid storage and mobilization

“…This suggests a role for Rab18 in promoting TG accumulation[73]. Evidence also exists to support a role for Rab18 in lipolysis[71],[74] and that Rab18 levels in adipose tissue correlate with obesity as well as with gender[75]. Despite being well characterized as a LD-associated protein, the function of Rab18 is yet to be determined.…”