Genetic ablation of phosphatidylcholine transfer protein/StarD2 in ob/ob mice improves glucose tolerance without increasing energy expenditure

Abstract

Objective: Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is highly expressed in liver and oxidative tissues. PC-TP promotes hepatic glucose production during fasting and aggravates glucose intolerance in high fat fed mice. However, because PC-TP also suppresses thermogenesis in brown adipose tissue (BAT), its direct contribution to obesity-associated diabetes in mice remains unclear. Here we examined the effects of genetic PC-TP ablation on glucose homeostasis in leptin-deficient ob/ob mice, which exhibit both diabetes and altered thermoregulation.

Animals/methods: Mice lacking both PC-TP and leptin (Pctp^-/-;ob/ob) were prepared by crossing Pctp^-/- with ob/+ mice. Glucose homeostasis was assessed by standard assays, and energy expenditure was determined by indirect calorimetry using a comprehensive laboratory animal monitoring system, which also recorded physical activity and food intake. Body composition was determined by NMR and hepatic lipids by enzymatic assays. Core body temperature was measured using a rectal thermocouple probe.

Results: Pctp^-/-;ob/ob mice demonstrated improved glucose homeostasis, as evidenced by markedly improved glucose and pyruvate tolerance tests, without changes in insulin tolerance. However, there were no differences in EE at any ambient temperature. There were also no effects of PC-TP expression on physical activity, food intake or core body temperature.

Conclusions: Improved glucose tolerance in Pctp^-/-;ob/ob mice in the absence of increases in energy expenditure or core body temperature indicates a direct pathogenic role for PC-TP in diabetes in leptin deficient mice.

Keywords: Diabetes; Insulin resistance; Leptin; Thermoregulation.

Figure 1

Genetic ablation of PC-TP decreases adiposity and improves glucose tolerance without altering hepatic lipid concentrations in ob/ob mice. (A) Body weights of male leptin-deficient mice at 10 w of age (ob/ob, n = 9; Pctp^−/−;ob/ob, n = 20). (B) Body composition assessed by NMR spectroscopy at 9 w of age and displayed as tissue mass (ob/ob, n = 11; Pctp^−/−;ob/ob, n = 11). (C) Liver size expressed as a percentage of bw. Hepatic concentrations of (D) triglycerides, (E), cholesterol and (F) free fatty acids. (G) Plasma glucose concentration following 6 or 16 h of food withdrawal (n = 12–13 per group). Tolerance tests to (H) glucose (7–8 w old mice), (I) pyruvate and (J) insulin (8–9 w old mice) were performed following 16 h (H, I) or 6 h (J) of food withdrawal, respectively, for mice housed at room temperature on chow diet (n = 12–13 for GTT and ITT; 6–8 for PTT). Values of area under the curve (AUC) are presented as inset barplots. Data are mean +/− SEM. *P < 0.05 Pctp^−/−;ob/ob vs. ob/ob.

Figure 2

PC-TP expression does not affect EE in absence of leptin. Values of (A) VO₂ and (B) VCO₂ were determined by indirect calorimetry (n = 11–14/group). Values of (C) EE and (D) RER were calculated from VO₂ and VCO₂ as described in section 2.3 of the text. Vertical dotted lines denote intervening 48 h equilibration periods. White background denotes light hours and gray denotes dark hours. (E) Cumulative EE values over 24 h were adjusted for lean body mass by ANCOVA. (F) Core body temperatures following 48 h acclimation. (G) Cumulative physical activity over 24 h. (H) Cumulative food intake. Data are mean +/− SEM.