Leptin Resistance Contributes to Obesity in Mice with Null Mutation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance. Consistently, mice with null mutation of Ceacam1 (Cc1 ؊/؊ ) exhibit impaired insulin clearance with increased lipid production in liver and redistribution to white adipose tissue, leading to visceral obesity at 2 months of age. When the mutation is propagated on the C57/BL6J genetic background, total fat mass rises significantly with age, and glucose intolerance and systemic insulin resistance develop at 6 months of age. This study was carried out to determine the mechanisms underlying the marked increase in total fat mass in 6-month-old mutants. Indirect calorimetry analysis showed that Cc1 ؊/؊ mice develop hyperphagia and a significant reduction in physical activity, in particular in the early hours of the dark cycle, during which energy expenditure is only slightly lower than in wildtype mice. They also exhibit increased triglyceride accumulation in skeletal muscle, due in part to incomplete fatty acid ␤-oxidation. Mechanistically, hypothalamic leptin signaling is reduced, as demonstrated by blunted STAT3 phosphorylation in coronal sections in response to an intracerebral ventricular injection of leptin. Hypothalamic fatty-acid synthase activity is also elevated in the mutants. Together, the data show that the increase in total fat mass in Cc1 ؊/؊ mice is mainly attributed to hyperphagia and reduced spontaneous physical activity. Although the contribution of the loss of CEACAM1 from anorexigenic proopiomelanocortin neurons in the arcuate nucleus is unclear, leptin resistance and elevated hypothalamic fatty-acid synthase activity could underlie altered energy balance in these mice.

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

“…To investigate whether the increase in hypothalamic FASN activity contributes to hyperphagia, we examined the effect of C75, a FASN inhibitor [28], on daily food intake. As shown in Heinrich et al [23], Cc1 −/− mice exhibit a higher daily food intake than Cc1 +/+ mice (Fig. 5e).…”

“…As shown in Fig. 4a, b, rescuing hepatic CEACAM1 reversed hyperphagia and physical inactivity in Cc1 −/− mice, respectively, in particular in the dark cycle when the phenotype is more pronounced [23]. As expected, there was no significant effect on heat production (Fig.…”

“…Cc1 −/− mice manifested progressively higher body weight than Cc1 +/+ mice in parallel to hyperphagia and reduced physical activity without significantly affecting energy expenditure (and heat production) at 5–6 months of age when they develop leptin [23] and insulin resistance [7]. To investigate whether insulin resistance contributes to energy imbalance, we subjected mice to indirect calorimetry.…”

“…Cc1 −/− mice also develop obesity and higher total fat mass by 6 months of age, owing to hyperphagia and low physical activity [23]. Reversal of this energy imbalance in parallel to restoring physiological insulin levels and hypothalamic insulin signalling in Cc1 −/− xliver + mice points to the contribution of hypothalamic insulin resistance in the energy imbalance of global Cc1 −/− mice, in support of the well-documented role of insulin in regulating food intake and physical activity [35–37], as well as insulin response in liver [38].…”

Reduced Hepatic Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Level in Obesity

“…Consistent with its positive effect on de novo lipogenesis (9), hyperinsulinemia also causes hepatic lipid accumulation, as well as lipid redistribution to the white adipose depot for storage, resulting in elevated visceral obesity. Contributing to visceral obesity and increased total fat mass in Cc1 −/− mice is leptin resistance, manifested by hyperphagia and reduced spontaneous physical activity (10). …”