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The gastrointestinal tract is involved in physiological regulation, including regulation of metabolism and feeding behavior, through the secretion of gut hormones and generation of signals via receptors in response to nutrients. Several G protein-coupled receptors (GPCRs) have been identified as sensors of lipids, such as fatty acids, monoacylglycerols (MAGs), and their metabolites, the levels of which are increased in the intestine after meals. GPR40 and 120 are well-known receptors for dietary long-chain fatty acids and their metabolites produced by gut microbiota. In addition, GPR119 is a receptor for MAGs [i.e. 2-oleoylglycerol (2-OG)], lysophosphatidylcholine (LPC), and fatty acid ethanolamides (FAEs) [i.e. oleoylethanolamide (OEA)]. Although enterocytes, enteroendocrine cells, and neural fibers have been postulated to sense lipids via GPCRs in the gut, most studies imply that enteroendocrine cells are the primary cells that sense lipids, which results in the production of hormones like cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) after a meal.

Miki Igarashi, Tetsuhiko Hayakawa, Haruka Tanabe, Keita Watanabe, ... Ikuo Kimura

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Current Issue

DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice

Charles Colas, Mathilde Mouchiroud, Manal Al Dow, Alona Kolnohuz, ... Mathieu Laplante

Objectives

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth and metabolism. In mice, activation of mTOR controls cold adaptation by promoting the recruitment and the activation of brown adipose tissue (BAT). DEP-domain containing mTOR-interacting protein (DEPTOR) interacts with mTOR to modulate its activity. Whether DEPTOR levels are modulated by cold in BAT and whether this protein regulates brown adipocyte development and thermogenic activation has never been tested.

Methods

DEPTOR levels were measured in mouse tissues upon cold exposure and in brown preadipocytes following the induction of adipogenesis. Lentiviruses expressing short-hairpin RNA were used to repress DEPTOR expression in brown preadipocytes in vitro. Conditional deletion of DEPTOR in brown preadipocytes and in mature brown fat cells was achieved by crossing DEPTOR floxed mice with either Myf5-Cre or Ucp1-CreERT2 mice. These animals were exposed to cold and extensively phenotyped.

Results

DEPTOR is highly expressed in BAT and its levels are induced by chronic cold exposure, a condition that triggers BAT expansion and activation. Supporting a role for DEPTOR in brown fat cell recruitment, we found that DEPTOR is induced during brown adipocyte development and that its depletion impairs adipogenesis in vitro. This adipogenic lesion was associated with defects in both Akt activation and the expression of key adipogenic regulators. Conditional deletion of DEPTOR in brown preadipocytes or mature brown fat cells did not impact BAT recruitment and thermogenesis in mice but slightly reduced the expression of adipogenic and lipogenic genes.

Conclusions

DEPTOR is highly expressed in BAT and its levels are dynamically regulated during brown fat cell development and upon cold exposure. Although DEPTOR depletion severely represses brown fat adipogenesis in vitro, its deletion is dispensable for BAT development, recruitment, and thermogenic activation in mice.

 

DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice

Charles Colas, Mathilde Mouchiroud, Manal Al Dow, Alona Kolnohuz, ... Mathieu Laplante

Objectives

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth and metabolism. In mice, activation of mTOR controls cold adaptation by promoting the recruitment and the activation of brown adipose tissue (BAT). DEP-domain containing mTOR-interacting protein (DEPTOR) interacts with mTOR to modulate its activity. Whether DEPTOR levels are modulated by cold in BAT and whether this protein regulates brown adipocyte development and thermogenic activation has never been tested.

Methods

DEPTOR levels were measured in mouse tissues upon cold exposure and in brown preadipocytes following the induction of adipogenesis. Lentiviruses expressing short-hairpin RNA were used to repress DEPTOR expression in brown preadipocytes in vitro. Conditional deletion of DEPTOR in brown preadipocytes and in mature brown fat cells was achieved by crossing DEPTOR floxed mice with either Myf5-Cre or Ucp1-CreERT2 mice. These animals were exposed to cold and extensively phenotyped.

Results

DEPTOR is highly expressed in BAT and its levels are induced by chronic cold exposure, a condition that triggers BAT expansion and activation. Supporting a role for DEPTOR in brown fat cell recruitment, we found that DEPTOR is induced during brown adipocyte development and that its depletion impairs adipogenesis in vitro. This adipogenic lesion was associated with defects in both Akt activation and the expression of key adipogenic regulators. Conditional deletion of DEPTOR in brown preadipocytes or mature brown fat cells did not impact BAT recruitment and thermogenesis in mice but slightly reduced the expression of adipogenic and lipogenic genes.

Conclusions

DEPTOR is highly expressed in BAT and its levels are dynamically regulated during brown fat cell development and upon cold exposure. Although DEPTOR depletion severely represses brown fat adipogenesis in vitro, its deletion is dispensable for BAT development, recruitment, and thermogenic activation in mice.

 

2021 impact factor: 8.568

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