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Parlakgul, Gunes

Proper function of the endoplasmic reticulum (ER) and mitochondria is critical for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states including metabolic diseases. Although ER and mitochondria play distinct cellular roles, these organelles also form physical interactions at sites defined as mitochondria associated ER-membranes (MAMs), which are essential for Ca2+, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a significant reorganization of MAMs resulting in mitochondrial Ca2+ overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, while down-regulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering and calcium transport respectively, improves mitochondrial oxidative capacity and insulin sensitivity in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity, which may contribute to the development of metabolic pathologies such as insulin resistance.

Objective Brown adipose tissue (BAT) generates heat in response to cold, and low BAT activity has been linked to obesity. However, recent studies were inconclusive as to whether BAT is involved in diet‐induced thermogenesis and mitigates weight gain from prolonged overeating. Therefore, this study investigated whether BAT activity is related to metabolic adaptation arising from 8 weeks of overfeeding in humans.

Methods Fourteen men (aged 24 ± 3 years, BMI 24.5 ± 1.6 kg/m2) were overfed by 40% for 8 weeks. Before and after, energy expenditure and metabolic adaptation were measured by whole‐room respiratory calorimetry. A marker of BAT activity was measured using infrared imaging of the supraclavicular BAT depot.

Results At the end of 8 weeks of overfeeding, metabolic adaptation—defined as the percent increase in sleeping energy expenditure beyond that expected from weight gain—rose from −0.9 ± 3.9% to 4.7 ± 5.6% (P = 0.001). However, BAT thermal activity was unchanged (P = 0.81). Moreover, BAT thermal activity did not correlate with the degree of metabolic adaptation (P = 0.32) or with the change in body weight (P = 0.51).

Conclusions BAT thermal activity does not change in response to overfeeding, nor does it correlate with adaptive thermogenesis. Our data suggest that BAT does not mediate metabolic adaptation to overeating in humans.

Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 10^5 μm^3) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found marked alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.