Changes in morphology and function of adrenal cortex in mice fed a high-fat diet

Swierczynska, Marta M.; Mateska, Ivona; Peitzsch, Mirko; Bornstein, Stefan R.; Chavakis, T; Eisenhofer, Graeme; Lamounier-Zepter, Valéria; Eaton, Suzanne

doi:10.1038/ijo.2014.102

Cited by 55 publications

(72 citation statements)

References 52 publications

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“…Importantly, the above abnormalities in the Western models strongly suggested the presence of inappropriate and impaired HPA feedback control with dysregulation between these neuroendocrine and systemic endocrine organs. These observations and findings in the Western model agreed with another study of the adrenal gland [31].…”

Section: Ofsupporting

confidence: 92%

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Hayden¹

2019

Preprint

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Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

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Section: Ofsupporting

confidence: 92%

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Hayden¹

2019

Preprint

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“…Diet-induced obesity elevates Shh signalling [38]. Extracellular vesicle-associated Shh forms have been described as the most important secreted forms of Shh [22].…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

Song

Han

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Adipocyte-derived exosomes (ADEs) stimulate the activation of macrophages and contribute to the development of insulin resistance. Sonic Hedgehog (Shh) is an exosome-carrying protein and stimulates macrophages to secrete inflammatory cytokines. However, the impact of ADEs carrying Shh on the pro-inflammatory activation of macrophages and consequently, adipocyte insulin resistance is unclear. Methods: 3T3-L1 adipocytes were cultured with high glucose and insulin to imitate the pathogeny of insulin resistance. ADEs were isolated from conditioned media of 3T3-L1 adipocytes via differential ultracentrifugation. We explored the role of ADEs carrying Shh in the polarization of macrophages by flow cytometry. Western blot and electrophoretic mobility shift assay (EMSA) were performed to determine the activation of Shh-mediated signalling pathways. The effects of ADE-treated macrophages on adipocyte insulin signalling were studied by Western blot. Results: We found that circulating Shh-positive exosomes were increased in type 2 diabetes patients. High glucose and insulin increased the secretion of Shh-positive ADEs. The ADEs carrying Shh induced pro-inflammatory or M1 polarization of bone marrow-derived macrophages (BMDM) and RAW 264.7 macrophages. Inhibitors of Ptch and PI3K blocked the M1 polarization induced by ADEs, which suggests that ADEs carrying Shh mediated M1 macrophage polarization through the Ptch/PI3K signalling pathway. ADE-treated RAW 264.7 macrophages were subsequently used to assess the effect on insulin signalling in adipocytes. Using a co-culture assay, we showed that both ADE-treated macrophages and exosomes from these macrophages could decrease the expression of insulin-resistant substrate-1 (IRS-1) and hormone-sensitive lipase (HSL) in adipocytes. Inhibitors of Ptch and PI3K blocked the down-regulation of IRS-1 and HSL induced by ADE-treated macrophages. Conclusion: Together, these data indicate that ADEs carrying Shh induce the M1 polarization of macrophages, which contributes to insulin resistance in adipocytes through the Ptch/PI3K pathway.

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“…Whether HFD feeding modulates (e.g., increases) the hepatic levels of the endogenous ligands of PXR or CAR (e.g., bilirubin, bile acids, and steroid hormones) (Bjorkholm et al, 2009) remains unclear. Of interest, HFD feeding was shown to cause adrenal cortical hyperplasia in mice, leading to higher plasma levels of corticosteroids (i.e., PXR activators) (Swierczynska et al, 2015).…”

Section: Downloaded Frommentioning

confidence: 99%

High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice

Ning

Jeong

2017

Drug Metab Dispos

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Medical conditions accompanying obesity often require drug therapy, but whether and how obesity alters the expression of drug-metabolizing enzymes and thus drug pharmacokinetics is poorly defined. Previous studies have shown that high-fat diet (HFD) feeding and subsequent obesity in mice lead to altered expression of transcriptional regulators for cytochrome P450 CYP2D6, including hepatocyte nuclear factor 4 (HNF4, a transcriptional activator of CYP2D6) and small heterodimer partner (SHP, a transcriptional repressor of CYP2D6). The objective of this study was to examine whether diet-induced obesity alters CYP2D6 expression by modulating HNF4 and SHP expression. Male CYP2D6-humanized transgenic (Tg-CYP2D6) mice were fed with HFD or matching control diet for 18 weeks. Hepatic mRNA expression of CYP2D6 decreased to a small extent in the HFD group (by 31%), but the differences in CYP2D6 protein and activity levels in hepatic S9 fractions were found insignificant between the groups. Although hepatic SHP expression did not differ between the groups, HNF4 mRNA and protein levels decreased by ∼30% in the HFD group. Among major mouse endogenous cytochrome P450 genes, Cyp1a2 and Cyp2c37 showed significant decreases in the HFD group, whereas Cyp2e1 expression did not differ between groups. Cyp2b10 and Cyp3a11 expression was higher in the HFD group, with corresponding 2.9-fold increases in hepatic CYP3A activities in HFD-fed mice. Together, these results suggest that obesity has minimal effects on CYP2D6-mediated drug metabolism, although it modulates the expression of mouse endogenous P450s in a gene-specific manner.

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Changes in morphology and function of adrenal cortex in mice fed a high-fat diet

Abstract: This work provides insight into how diet-induced obesity changes the biology of the adrenal gland. The association of these changes with increased Shh signaling suggests possible therapeutic strategies for obesity-related steroid hormone dysfunction.

Cited by 55 publications

References 52 publications

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice

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