Background: CEACAM1 regulates insulin sensitivity by promoting insulin clearance. Accordingly, global C57BL/6J.Cc1 −/− null mice display hyperinsulinemia due to impaired insulin clearance at 2 months of age, followed by insulin resistance, steatohepatitis, visceral obesity and leptin resistance at 6 months. The study aimed at investigating the primary role of hepatic CEACAM1 in insulin and lipid homeostasis independently of its metabolic effect in extra-hepatic tissues. Methods: Liver-specific C57BL/6J.AlbCre+Cc1 fl/fl mice were generated and their metabolic phenotype was characterized by comparison to that of their littermate controls at 2-9 months of age, using hyperinsulinemic-euglycemic clamp analysis and indirect calorimetry. The effect of hyperphagia on insulin resistance was assessed by pair-feeding experiments.

Insulin resistance and obesity are associated with reduced gonadotropin-releasing hormone (GnRH) release and infertility. Mice that lack insulin receptors (IRs) throughout development in both neuronal and non-neuronal brain cells are known to exhibit subfertility due to hypogonadotropic hypogonadism. However, attempts to recapitulate this phenotype by targeting specific neurons have failed. To determine whether astrocytic insulin sensing plays a role in the regulation of fertility, we generated mice lacking IRs in astrocytes (astrocyte-specific insulin receptor deletion [IRKO GFAP ] mice). IRKO GFAP males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. In adulthood, IRKO GFAP female mice also exhibited longer, irregular estrus cycles, decreased pregnancy rates, and reduced litter sizes. IRKO GFAP mice show normal sexual behavior but hypothalamic-pituitary-gonadotropin (HPG) axis dysregulation, likely explaining their low fecundity. Histological examination of testes and ovaries showed impaired spermatogenesis and ovarian follicle maturation. Finally, reduced prostaglandin E synthase 2 (PGES2) levels were found in astrocytes isolated from these mice, suggesting a mechanism for low GnRH/luteinizing hormone (LH) secretion. These findings demonstrate that insulin sensing by astrocytes is indispensable for the function of the reproductive axis. Additional work is needed to elucidate the role of astrocytes in the maturation of hypothalamic reproductive circuits.

G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 "interactome" that underlies a great diversity in its functional roles. Several such GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for heart failure therapy. Herein, we subjected transgenic mice with cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) to pressure overload and found that unlike their littermate controls or previous GRK2 fragments, they exhibited an increased left ventricular wall thickness and mass prior to cardiac stress that underwent proportional hypertrophic growth to controls after acute pressure overload. Importantly, despite this enlarged heart, βARKnt mice did not undergo the expected transition to heart failure observed in controls. Further, βARKnt expression limited adverse left ventricular remodeling and increased cell survival signaling. Proteomic analysis to identify βARKnt binding partners that may underlie the improved cardiovascular phenotype uncovered a selective functional interaction of both endogenous GRK2 and βARKnt with AKT substrate of 160 kDa (AS160). AS160 has emerged as a key downstream regulator of insulin signaling, integrating physiological and metabolic cues to couple energy demand to membrane recruitment of Glut4. Our preliminary data indicate that in βARKnt mice, cardiomyocyte insulin signaling is improved during stress, with a coordinate increase in spare respiratory activity and ATP production without metabolite switching. Surprisingly, these studies also revealed a significant decrease in gonadal fat weight, equivalent to human abdominal fat, in male βARKnt mice at baseline and following cardiac stress. These data suggest that the enhanced AS160-mediated signaling in the βARKnt mice may ameliorate pathological cardiac remodeling through direct modulation of insulin signaling within cardiomyocytes, and translate these to beneficial effects on systemic metabolism.

The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IRKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as two months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IRKOGFAP males. Less innervation and lower βAR3 expression levels were also observed in IRKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte IR deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

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Atrial fibrillation (AF) is the most common arrhythmia and a major risk factor for cardiovascular mortality and stroke. Despite significant advances in AF diagnosis and management, major gender discrepancies in treatment and clinical outcomes remain. It is unclear if these are related to treatment disparities or to underlying differences in the structure and biochemical makeup of the female versus male heart. How lifestyle, diet, comorbidities and risk factors contribute to this clinical dimorphism are not well understood. My laboratory has recently developed a double-transgenic mouse line that recapitulates this gender dimorphism. These mice were generated by crossing lines with cardiac expression of an amino and carboxyl terminal fragment, βARKnt (residues 50-145) and βARKct (residues 495-689), of the prototypical G protein-coupled receptor (GPCR) kinase GRK2 (originally βARK1). This line was created to investigate the therapeutic potential of dual regulation of β-adrenergic receptor signaling independent of canonical GRK2 activity. Since preliminary data demonstrate atrial dysfunction in both genders, but structural remodeling in females only, this model presents a unique tool to investigate sex differences in the molecular and cellular mechanisms of atrial remodeling. Masson’s trichrome staining of 4-chamber paraffin sections demonstrated an increase in wall thickness in the βARKnt and βARKnt/βARKct mice in agreement with the increased heart weight. Interestingly, these data revealed a significant increase in left and right atrial size in the double transgenic female hearts only, with no apparent alteration in the male atria. Preliminary echo recordings demonstrated significant alterations in E/A ratio (ventricular relaxation/atrial contraction) in the βARKnt and even more pronounced in the βARKnt/βARKct male and female mice. These data suggest that although no remodeling is evident at baseline, the male βARKnt/βARKct mice have underlying atrial dysfunction that may be more susceptible to additional cardiovascular stress. A better understanding of gender differences in the underlying mechanisms of atrial susceptibility may facilitate the development of safer and more effective approaches for AF management and prevention.