FNIP1 regulates adipocyte browning and systemic glucose homeostasis in mice by shaping intracellular calcium dynamics

Abstract

Metabolically beneficial beige adipocytes offer tremendous potential to combat metabolic diseases. The folliculin interacting protein 1 (FNIP1) is implicated in controlling cellular metabolism via AMPK and mTORC1. However, whether and how FNIP1 regulates adipocyte browning is unclear. Here, we demonstrate that FNIP1 plays a critical role in controlling adipocyte browning and systemic glucose homeostasis. Adipocyte-specific ablation of FNIP1 promotes a broad thermogenic remodeling of adipocytes, including increased UCP1 levels, high mitochondrial content, and augmented capacity for mitochondrial respiration. Mechanistically, FNIP1 binds to and promotes the activity of SERCA, a main Ca2+ pump responsible for cytosolic Ca2+ removal. Loss of FNIP1 resulted in enhanced intracellular Ca2+ signals and consequential activation of Ca2+-dependent thermogenic program in adipocytes. Furthermore, mice lacking adipocyte FNIP1 were protected against high-fat diet–induced insulin resistance and liver steatosis. Thus, these findings reveal a pivotal role of FNIP1 as a negative regulator of beige adipocyte thermogenesis and unravel an intriguing functional link between intracellular Ca2+ dynamics and adipocyte browning.

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

“…Specifically, FNIP1 was shown to regulate intracellular Ca 2+ levels through stabilization of sarcoendoplasmic reticulum calcium transport ATPase (SERCA) and increasing SERCA Ca 2+ pump activity. This study also suggested a pivotal role for FNIP1 in regulating metabolism and glucose homeostasis in adipocytes, independent of AMPK/mTOR [ 35 ].…”

“…These data provide a mechanism that explains the FNIP1-dependent regulation of AMPK in skeletal muscle. FNIP1 regulation of AMPK may be cell-type dependent however, as recent work has demonstrated that FNIP1 regulates cellular respiration in adipocytes in an AMPK/mTOR independent manner [35]. Specifically, FNIP1 was shown to regulate intracellular Ca 2+ levels through stabilization of sarcoendoplasmic reticulum calcium transport ATPase (SERCA) and increasing SERCA Ca 2+ pump activity.…”

Comments on ‘FNIP1 regulates adipocyte browning and systemic glucose homeostasis in mice by shaping intracellular calcium dynamics’

“…In summary, our recent work suggests that FNIP1 acts as a negative regulator of beige adipocyte thermogenesis to control systemic glucose homeostasis through modulating SERCA ( Yin et al, 2022 ). Linking intracellular Ca 2+ dynamics to adipocyte beiging is of interest, given that it could be an appealing strategy for the treatment of metabolic disorders.…”

“…In our recent work ( Yin et al, 2022 ), we discovered a previously unrecognized WAT beiging mechanism that targets the folliculin (FLCN) interacting protein 1 (FNIP1)–sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA)–intracellular Ca 2+ axis in adipocytes ( Figure 1 ; commented in Bunk and Kazak, 2022 ). Using multiple Ca 2+ imaging approaches, together with gain- and loss-of-function strategies, we provided clear data demonstrating that FNIP1 is a crucial regulator of intracellular Ca 2+ dynamics and negatively regulates WAT beiging.…”

Calcium burns beige

“…Calcium (Ca 2 + ) influx into thermogenic adipocytes is regulated by extrinsic adrenergic control ( Chen et al, 2017 ), but a deep mechanistic understanding for how Ca 2+ signaling regulates adaptive thermogenesis is far from complete. Yin et al (2022) identify one piece of the adaptive thermogenesis puzzle by providing evidence that folliculin interacting protein 1 (FNIP1) negatively regulates the browning of white fat by dampening cytosolic Ca 2+ levels. The sarcoendoplasmic reticulum calcium transport ATPase (SERCA) pump is the regulator of Ca 2+ uptake from the cytosol to the ER.…”