Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms

Abstract

Highlights d Hepatic AKT is activated in response to cold exposure and b 3 adrenergic stimulation d Lack of AKT in liver leads to cold sensitivity d Hepatic AKT signaling via FOXO1 induces FGF21 expression d FOXO1 cell-nonautonomously regulates adipose tissue thermogenesis

Determination of tissue contributions to the circulating lipid pool in cold exposure via systematic assessment of lipid profiles

“…2 C). Cers are known to communicate cellular identity as well as regulate insulin signaling and fatty acid oxidation ( 43 , 44 ). There was a significant increase in total Cers in plasma and liver but not BAT during cold exposure, though the overall level of Cers was higher in BAT than plasma or liver regardless of temperature ( Figs.…”

“…Cers have been shown to regulate differentiation in brown and beige adipocytes, and adipose tissue-specific knockout of Cer synthesis enzyme Sptlc2 led to decreased Cers, increased mitochondrial content, increased respiration, and increased thermogenic transcript expression ( 36 , 37 , 43 , 51 ). Conversely, loss of Cer degradation through knockout of acid ceramidase 1 driven by the uncoupling protein 1 promoter led to increased Cer levels, decreased mitochondria, decreased respiration, and decreased thermogenic transcripts ( 37 ).…”

“…Acute treatment of beige adipocytes with a sphingolipid synthesis inhibitor, myriocin, increased cellular respiration, whereas increasing Cer levels by treating beige adipocytes with C 2 -Cer led to decreased respiration ( 36 ). Beyond regulation of differentiation and respiration, Cer species are known to regulate insulin sensitivity ( 43 , 51 , 52 ). Perhaps in acute cold exposure, where a rapid shift from glucose to lipid catabolism is needed to conserve glucose stores for the brain, Cer-induced insulin resistance confers an adaptive advantage.…”

Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity

“…Next, we determined if FoxO1 activity was sufficient to repress Gm11967 expression. Here, we utilized a mouse model of liver-specific constitutive FoxO1 activity where the Akt-dependent phosphorylation sites are mutated to prevent Akt-mediated phosphorylation and inhibition of FoxO1 (L-FoxO1 AAA) ( Zhang et al., 2006 ; Sostre-Colón et al., 2021 ). Consistent with the role of FoxO1 in the direct regulation of Gm11967 , L-FoxO1 AAA mice had reduced levels of Gm11967 and Gck ( Figure 3 G).…”

Coexposure of Cyclopiazonic Acid with Aflatoxin B1 Involved in Disrupting Amino Acid Metabolism and Redox Homeostasis Causing Synergistic Toxic Effects in Hepatocyte Spheroids

“…The AKT gene has an important role in activating the PI3K/AKT signaling pathway, which is involved in the control of cell viability and proliferation and inhibits apoptosis. , The AKT gene expression in AFB1 + CPA coexposure was consistent with changes in the combined/antagonistic effect. Moreover, we continued to explore the mechanism of AFB1 + CPA toxicity by expressing the AKT gene as an apoptosis-suppressing gene.…”