Attenuated mTOR Signaling and Enhanced Autophagy in Adipocytes from Obese Patients with Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is strongly linked to obesity and an adipose tissue unresponsive to insulin. The insulin resistance is due to defective insulin signaling, but details remain largely unknown. We examined insulin signaling in adipocytes from T2D patients, and contrary to findings in animal studies, we observed attenuation of insulin activation of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). As a consequence, mTORC1 downstream effects were also affected in T2D: feedback signaling by insulin to signal-mediator insulin receptor substrate-1 (IRS1) was attenuated, mitochondria were impaired and autophagy was strongly upregulated. There was concomitant autophagic destruction of mitochondria and lipofuscin particles, and a dependence on autophagy for ATP production. Conversely, mitochondrial dysfunction attenuated insulin activation of mTORC1, enhanced autophagy and attenuated feedback to IRS1. The overactive autophagy was associated with large numbers of cytosolic lipid droplets, a subset with colocalization of perlipin and the autophagy protein LC3/atg8, which can contribute to excessive fatty acid release. Patients with diagnoses of T2D and overweight were consecutively recruited from elective surgery, whereas controls did not have T2D. Results were validated in a cohort of patients without diabetes who exhibited a wide range of insulin sensitivities. Because mitochondrial dysfunction, inflammation, endoplasmic-reticulum stress and hypoxia all inactivate mTORC1, our results may suggest a unifying mechanism for the pathogenesis of insulin resistance in T2D, although the underlying causes might differ. the dephosphorylation by phosphotyrosine protein phosphatases (13).TOR coordinates control of cell growth and metabolism in accordance with nutrient availability in unicellular organisms. During evolution of multicellular organisms this control was seized by insulin and other growth factors. However, the ancient ability of TOR to sense nutrient levels in cells independently of insulin is retained in multicellular organisms, including man, giving TOR a key role in cellular control of metabolism and cell growth, as well as tolerance to starvation through control of autophagy. In mammalian cells mTOR, in complex with the protein raptor (mTORC1), is activated by insulin and the insulin receptor substrate-1 (IRS1) via either or both of the two signaling branches of insulin that lead to activation of protein kinase B/Akt or the Map-kinase ERK1/2, respectively. By responding to amino acid and energy levels in the cell, mTORC1 thus integrates insulin signaling with nutrient availability to control cellular processes such as cell growth, protein synthesis, mitochondrial function and autophagy ( Figure 1A), reviewed in (14). In several studies, in particular on animals after high-fat feeding regimens, insulin resistance has been coupled with hyperactive mTORC1 (reviewed in [6]). However, because mTORC1 mediates the positive feedback signal to phosphorylation of IRS1 at serine 307, we wanted to further...

FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

“…Given that FoxO1 is activated by insulin resistance 20,46,47 , the FoxO1-autophagy-FSP27 axis may promote LD and adipocyte expansion in obese insulin resistant subjects, thereby casting light on the pathological relevance of augmented autophagy in adipose tissues from obese subjects. [7][8][9][10][11][12] To the best of our knowledge, this is also the first study investigating the role of FoxO1 in the regulation of adipose autophagy.…”

“…6 Recent studies show that increased adiposity is associated with augmented autophagy in the adipose tissue from obese and type 2 diabetic humans and rodents. [7][8][9][10][11][12][13][14] Genetic suppression of autophagy by targeting autophagy related 5 (Atg5) or Atg7 in adipose tissue reduces adipocyte size, increases energy expenditure, and protects mice against diet-induced obesity. [15][16][17] Moreover, deletion of Atg5 suppresses adipogenesis (de novo formation of adipocytes).…”

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

“…However, the mechanisms of this defect could be diverse. Since obesity is characterized with enhanced intracellular lipid accumulation (Ost et al 2010), the role of progranulin with sustained lipogenesis might be much more complicated than expected. It is plausible that chronic lipid overloading, which might impair insulin signaling and insulin-stimulated glucose uptake, might be one of the triggers in metabolic disturbance.…”

Distinct functions ofUlk1andUlk2in the regulation of lipid metabolism in adipocytes

“…1,2 Recent studies have shown that autophagy is upregulated in adipocytes from diabetic mice or obese patients. [3][4][5][6][7][8] Adipose-specific deletion of a key autophagy gene, such as atg5 or atg7, led to lean mice and improved insulin sensitivity and glucose homeostasis in the whole body of mice. 6,7,9 One of the key features with the mouse models was a reduction in the white adipose tissue (WAT) mass, and an increase in the brown adipose tissue (BAT) mass.…”