The adipocyte supersystem of insulin and cAMP signaling

Guilherme, Adı́lson; Rowland, Leslie A.; Wang, Hui; Czech, Michael P.

doi:10.1016/j.tcb.2022.07.009

Cited by 23 publications

(12 citation statements)

References 120 publications

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“…Consistent with the GO analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the predicted functions of upregulated genes participated in various metabolic pathways and fatty acid oxidation, which is involved in mitochondrial thermogenesis (fig. S3C) ( 60 ). Among the upregulated genes influenced by E2, we noticed a clear increase in the expression of genes related to the NAD+ pathway, which was further validated by qPCR (Fig.…”

Section: Resultsmentioning

confidence: 99%

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Park,

Hu,

Xiong

et al. 2023

Preprint

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Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging-related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process.

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Section: Resultsmentioning

confidence: 99%

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Park,

Hu,

Xiong

et al. 2023

Preprint

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“…β 3 -AR is the predominant receptor expressed in brown adipose tissue and is critical for adaptive thermogenesis [23]. As shown in Figure 2A,B, different concentrations of FZL and a commercial selective β 3 -AR agonist BRL both increased the mitochondrial temperature of brown fat cells (BFCs), whereas these responses were attenuated after treatment with Prop.…”

Section: Fzl Stimulated Thermogenesis Through Activation Of β 3 -Arsmentioning

confidence: 97%

“…LPL gene expression and activity markedly increase in BAT upon activation of NST [21], causing a concomitant increase in TRL-derived fatty acid uptake, which accounts for approximately 50% of the whole-body TRL clearance [22]. The process of lipolysis and thermogenesis in white and brown adipocytes is mediated by β 3 -AR [23]. In response to β 3 -AR activation, cAMP-dependent protein kinase (PKA) phosphorylates hormone-sensitive lipase (HSL), which accelerates FA production and promotes the expression of thermogenic genes such as UCP1 [24].…”

Section: Introductionmentioning

confidence: 99%

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Fuziline Ameliorates Glucose and Lipid Metabolism by Activating Beta Adrenergic Receptors to Stimulate Thermogenesis

Gao

Cheng

et al. 2023

IJMS

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Radix aconiti carmichaeli is a widely used traditional Chinese medicine that has been found to be effective in treating cardiovascular diseases and metabolic disorders. Patients with these diseases often experience a heat generation disorder, which is characterized by chilliness and can worsen the progression of the disease. This study established an in vitro screening model combining the examination of cellular mitochondrial membrane potential and mitochondrial temperature to screen drugs with thermogenic activity. After differentiation and determination of the content of characteristic metabolites of the drug-containing serum blood components, it was found that Fuziline (FZL) is the key thermogenic property in Radix aconiti carmichaeli, responsible for its thermogenic effects with a high relative importance of 33%. Experiments were conducted to evaluate the thermogenic activity of Radix aconiti carmichaeli and FZL in vivo by assessing temperature changes in various organs, including the rectum, liver, and brown adipose tissue. Moreover, the effects of intracellular β3-adrenergic receptor (β3-AR) agonistic effects were evaluated using transient β3-AR transfection and dual-luciferase assay systems. The molecular mechanism by which FZL promotes thermogenesis and improves mitochondrial function was investigated by verifying the β-adrenergic receptors (β-AR) downstream signaling pathway. The results suggest that FZL activates β-AR nonselectively, which in turn activates the downstream cAMP-PKA signaling pathway and leads to an increase in liver glycogenolysis and triglyceride hydrolysis, accompanied by enhancing mitochondrial energy metabolism. Consequently, the liver and brown adipose tissue receive energy to generate heat. In summary, these findings provide insight into the therapeutic application of Radix aconiti carmichaeli for metabolic disorders associated with heat generation disorders.

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“…Furthermore, we have found that in humans with different adiposity and insulin sensitivity, fasting plasma insulin was not associated with blood glucose but was associated with adipose tissue lipolysis (Fryk et al, 2021). Considering the opposing actions of β-adrenergic signaling and InsR-PI3K signaling on adipocyte lipolysis (Guilherme et al, 2022; Solinas and Becattini, 2022), we hypothesized that insulin secretion is governed by adipocyte InsR-PI3K signaling.…”

Section: Introductionmentioning

confidence: 99%

Adipocyte PI3K Links Adipostasis with Basal Insulin Secretion Through an Adipoincretin Effect

Becattini

Molinaro

Henricsson

et al. 2023

Preprint

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Inhibitors of insulin-PI3K signaling potently induce insulin secretion in-vivo, demonstrating that insulin secretion is governed by feedback control. Resolving the mechanism of this feedback is necessary to understand hyperinsulinemia and insulin resistance and to develop optimal PI3K-targeted therapies. Adipose tissue-specific knockout mice for the insulin receptor, or AKT1 and AKT2, are severely lipodystrophic. Thereby, the role of adipocyte insulin signaling in the feedback control of insulin secretion remains unknown. To investigate insulin-PI3K signaling in the adipocyte in vivo, we generated adipocyte-specific PI3Kalpha knockout mice (PI3K alphaAdQ). PI3Kalpha AdQ mice and PI3Kalpha F/F control mice showed similar adiposity, indicating compensation from another PI3K activity. PI3Kbeta-selective inhibitors dumped AKT phosphorylation, specifically in the adipocytes of PI3K alpha AdQ mice. The PI3Kbeta-selective inhibitor GSK2636771 markedly increased serum FFA and insulin secretion in PI3Kalpha AdQ mice but not in PI3KalphaF/F mice, demonstrating that insulin secretion is governed by adipocyte PI3K, a phenomenon that we name the adipoincretin effect. The adipoincretin effect can be induced in mice fasted overnight with decreasing glycemia. The effects of adipocyte-specific PI3K inhibition on insulin secretion and serum FFA could be partly dissociated by cotreating PI3Kalpha AdQ mice with GSK2636771 and the lipolysis inhibitor nicotinic acid. The adipoincretin effect was associated with reduced plasma branched-chain amino acids, reduced serum leptin, and increased 3-hydroxybutyrylcarnitine. These results demonstrate that baseline insulin secretion and lipolysis are coregulated by adipocyte PI3K signaling to control adipostasis during fasting through an adipoincretin effect.

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The adipocyte supersystem of insulin and cAMP signaling

Cited by 23 publications

References 120 publications

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Fuziline Ameliorates Glucose and Lipid Metabolism by Activating Beta Adrenergic Receptors to Stimulate Thermogenesis

Adipocyte PI3K Links Adipostasis with Basal Insulin Secretion Through an Adipoincretin Effect

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