ProlongedNrf1overexpression triggers adipocyte inflammation and insulin resistance

Abstract

Adipose tissue is currently being recognized as an important endocrine organ, carrying defects in a number of metabolic diseases. Mitochondria play a key role in normal adipose tissue function and mitochondrial alterations can result in pathology, like lipodystrophy or type 2 diabetes. Although Pgc1α is regarded as the main regulator of mitochondrial function, downstream Nrf1 is the key regulator of mitochondrial biogenesis. Nrf1 is also involved in a wide range of other processes, including proliferation, innate immune response, and apoptosis. To determine transcriptional targets of Nrf1, 3T3-L1 preadipocytes were transfected with either pNrf1 or a control vector. Two days post-confluence, 3T3-L1 preadipocytes were allowed to differentiate. At day 8 of differentiation, Nrf1 overexpressing cells had an increased mtDNA copy number and reduced lipid content. This was not associated with an increased ATP production rate per cell. Using global gene expression analysis, we observed that Nrf1 overexpression stimulated cell proliferation, apoptosis, and cytokine expression. In addition, prolonged Nrf1 induced an adipokine expression profile of insulin resistant adipocytes. Nrf1 has a wide range of transcriptional targets, stimulators as well as inhibitors of adipose tissue functioning. Therefore, post-transcriptional regulation of Nrf1, or stimulating specific Nrf1 targets may be a more suitable approach for stimulating mitochondrial biogenesis and treating adipose tissue defects, instead of directly stimulating Nrf1 expression. In addition, our results show that short-term effects can drastically differ from long-term effects.

Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion‐weighting: Diffusion in long fibers (almost) accounts for non‐monoexponential attenuation

“…When analyzing NAA signal acquired at longer TE with the randomly oriented cylinders model (Fig.4b and Table 2), the model returns a =0.62±0.12 µm (and D intra cyl =0.335±0.021 µm 2 /ms), which is now realistic and very close to the radius extracted for glutamate, strongly suggesting that a highly restricted NAA pool has become invisible. Going one step further, these a and D intra cyl values can be injected in a modified model, where a log-normal distribution of spherical compartments (accounting for organelles/mitochondria size distribution in healthy cells (27,28) ) is added to cylinders whose properties were determined at long TE, to fit data at short TE (Fig. 4a-b).…”

Age-associated declines in mitochondrial biogenesis and protein quality control factors are minimized by exercise training

“…PNPase plays a crucial role in mitochondrial RNA import (61); however, the upregulation of PNPase could induce inflammation by interferon-mediated degradation of specific mRNAs and small noncoding RNAs (51). Interestingly, NRF1 overexpression has also been associated with inflammation (59). Aging is associated with increased levels of inflammation (41), and there is limited data suggesting that PNPase could play a role in cellular senescence (32).…”

Milk-Derived Tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) Promote Adipocyte Differentiation and Inhibit Inflammation in 3T3-F442A Cells

“…Under normal conditions, insulin promotes adipocyte differentiation involving incorporation of neutral lipids (such as triglycerides) into these cells, upregulation of the anti-inflammatory metabolic modulator peroxisome proliferator-activated receptor gamma (PPARγ) and secretion of the beneficial adipokine (hormone from fat tissue) adiponectin [ 14 – 17 ]. Under pathological conditions such as metabolic syndrome, these normal effects of insulin are perturbed, leading to abnormal adipogenesis as characterized by lack of differentiation in adipocyte precursors (pre-adipocytes), increased inflammation in such cells and higher levels of circulating lipids in the bloodstream [ 18 – 21 ]. Hence, compounds that can induce adipogenic differentiation in pre-adipocytes may improve insulin sensitivity and/or act as insulin-mimetics which would potentially improve the management of conditions such as metabolic syndrome [ 22 – 24 ].…”