Role of adipose mTORC2 in mature adipocytes and whole-body energy homeostasis

Mammalian target of rapamycin complex 2 (mTORC2) is a protein kinase complex that
optimizes anabolic and catabolic cellular processes in response to environmental cues to
maintain energy homeostasis. mTORC2 is ubiquitously expressed, and its dysregulation is
associated with metabolic disorders such as obesity and type II diabetes. In white adipose
tissue (WAT), mTORC2 signaling promotes various insulin-dependent processes including
glucose uptake and de novo lipogenesis (DNL). Loss of adipose mTORC2 not only impairs
adipocyte metabolism, but also disrupts whole-body energy homeostasis.
In order to better understand the role of adipose mTORC2 in whole-body energy
homeostasis, we generated tamoxifen-inducible adipose-specific RICTOR knockout
(iAdRiKO) mice. We found that ablation of RICTOR, an essential component of mTORC2,
in mature adipocytes causes hyperinsulinemia, systemic insulin resistance and aberrant liver
AKT signaling. Since loss of adipose mTORC2 rapidly alters phosphorylation of proteins
associated with the plasma membrane and involved in synapse formation, we hypothesized
that adipose mTORC2 regulates inter-organ communication via the peripheral nervous
system. We established a whole-adipose tissue clearing and imaging method to visualize the
sensory and sympathetic neuronal network in WAT. We discovered that adipose mTORC2 is
essential for arborization of sensory neurons, but not sympathetic neurons. Further
investigation could not confirm a role for sensory neurons in the regulation of whole-body
energy homeostasis, although a more suitable mouse model is required to definitely confirm
these observations.
We also demonstrate that loss of adipose mTORC2 impairs the capacity of WAT to import
and store excess energy. As a result, mice lacking adipose mTORC2 develop mild
lipodystrophy and accumulate triglycerides (TGs) in the liver due to increased DNL. Blocking
hepatic DNL and TG accumulation in the absence of adipose mTORC2 signaling has a
detrimental effect on whole-body energy homeostasis, resulting in severe insulin resistance
and glucose intolerance. We conclude that mTORC2 ablation in adipocytes impairs energy
storage in WAT and the subsequent increase in hepatic DNL is a physiological response to
compensate for impaired WAT function.
Although we cannot exclude that mTORC2 regulates whole-body energy homeostasis via an
unknown adipokine or sensory activity, our data suggests that adipose mTORC2 contributes
to whole-body energy homeostasis by promoting the core function of WAT, namely the
storage of excess energy