Our data show that PI3K-C2α activity is critical for leptin signalling in the brain. Interestingly, a previous study has presented evidence for leptin-induced activation of PI3K-C2α in macrophages [
42]. In addition to actions in the brain, leptin also directly acts on multiple peripheral tissues, including pancreatic islets, liver, adipose tissue, kidney and skeletal muscle [
43,
44]. However, genetic deletion of the leptin receptor in these tissues does not alter energy balance, body weight or glucose homeostasis [
43,
44], highlighting a more critical role for leptin signalling in the brain with regards to organismal metabolism.
Leptin has also been shown to play an important role in renal pathophysiology [
45,
46]. Despite a small decrease in the relative weight of the kidneys in aged C2α
D1268A/WT male mice in relation to overall body weight, we did not observe any histopathological abnormalities in the kidneys of male or female heterozygous C2α
D1268A/WT mice. However, previously described PI3K-C2α gene-trap mice, which have >75% reduction in organismal PI3K-C2α activity, develop chronic renal failure and a range of kidney lesions, even at a young age [
15]. It would be interesting to assess whether a metabolic phenotype is also observed in PI3K-C2α gene-trap mice and whether leptin resistance in kidney cells could contribute to their kidney phenotype.
Finally, the sexual dimorphism of the leptin resistance phenotype in the C2α
D1268A/WT mice is in line with the known sexual dimorphism in leptin biology in rodents or humans at the level of serum leptin levels, leptin receptor expression and signalling [
29]. Indeed, serum leptin and receptor levels are significantly higher in female mice than in male with equivalent body fat mass [
30], which might render females less sensitive to dysfunctions in leptin signalling.
At present, the mechanism of leptin resistance in the male C2α
D1268A/WT mice is unclear. Leptin resistance can be due to a multitude of mechanisms, including defective leptin transport from the blood circulation to the brain, defective hypothalamic neural circuitry that regulates energy homeostasis and/or altered leptin signalling [
44]. Leptin-induced Stat3 phosphorylation was found to be reduced in the hypothalamus in C2α
D1268A/WT mice, indicating that the defect occurs at the level of LEPR signalling. PI(3)P and PI(3,4)P
2 are lipid products of PI3K-C2α that have been implicated in intracellular vesicular transport, including endocytosis and exocytosis [
5,
6]. Importantly, PI3K-C2α has been shown to be concentrated in the trans-Golgi network [
47]. It is therefore tempting to speculate that PI3K-C2α is involved in LEPR trafficking. LEPRb, the functional isoform of the leptin receptor, mainly resides in the trans-Golgi network and endosomes, with only a relatively small number of receptors on the plasma membrane to mediate leptin signalling [
44]. Interestingly, deletion of Bardet-Biedl syndrome (BBS) proteins, known to promote LEPRb trafficking, impairs leptin signalling and results in leptin resistance and obesity, both in mouse models and in humans [
48‐
50]. In addition to regulating LEPRb trafficking, BBS proteins also play a critical role in the regulation of cilia length as shown in renal medullary cells [
51]. In these cells, inactivation of BBS proteins leads to shorter cilia, a phenotype also observed in PI3K-C2α heterozygote KO mice [
14]. Cilia are important cellular structures that regulate signalling cascades that affect feeding and satiety [
52] but are not directly involved in leptin signalling [
53]. Conversely, leptin levels have been shown to regulate neuronal cilia length [
52]. Altogether, these data point to a potential role for BBS proteins downstream of PI3K-C2α, impacting both on leptin signalling and cilia length, which could directly and indirectly, respectively, affect organismal metabolism.
In summary, our studies describe the phenotypic characterisation of the first mouse model with a kinase-dead PI3K-C2α and reveal a role for this PI3K in organismal leptin signalling and age-dependent regulation of glucose homeostasis in males.