Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care

Pillon, Nicolas; Loos, Ruth J.F.; Marshall, Sally M.; Zierath, Juleen R.

doi:10.1016/j.cell.2021.02.012

Cited by 122 publications

(71 citation statements)

References 127 publications

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“…With the global obesity epidemic (Pillon et al, 2021), the resulting high rates of type 2 diabetes drive chronic injury and damage to many organs, including the kidney. We focused on diabetic kidney disease (DKD), or diabetic nephropathy, a devastating complication affecting at least 1 in 3 diabetics (https://www.cdc.gov/diabetes).…”

Section: Introductionmentioning

confidence: 99%

Obesity-instructed TREM2^high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

Subramanian

Vernon

Zhou

et al. 2021

Preprint

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Mouse models are a tool for studying the mechanisms underlying complex diseases; however, differences between species pose a significant challenge for translating findings to patients. Here, we used single-cell transcriptomics and orthogonal validation approaches to provide cross-species taxonomies, identifying shared broad cell classes and unique granular cellular states, between mouse and human kidney. We generated cell atlases of the diabetic and obese kidney using two different mouse models, a high-fat diet (HFD) model and a genetic model (BTBR ob/ob), at multiple time points along disease progression. Importantly, we identified a previously unrecognized, expanding Trem2high macrophage population in kidneys of HFD mice that matched human TREM2high macrophages in obese patients. Taken together, our cross-species comparison highlights shared immune and metabolic cell-state changes.

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Section: Introductionmentioning

confidence: 99%

Obesity-instructed TREM2^high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

Subramanian

Vernon

Zhou

et al. 2021

Preprint

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“…Treating obesity has proven to be a difficult task due to the multifactorial nature of the disease. Environmental factors (diet, temperature, physical and psychological stress, sleep quality, and physical activity), genetics, and epigenetics all play a role in the onset of obesity, though the main cause is a chronic imbalance between the amount of energy absorbed from food and the energy expended [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of AMPK Signaling in Brown Adipose Tissue Activation

Vaart

Boon

Houtkooper

2021

Cells

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Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

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“…Obesity is a chronic progressive disease with remissions and relapses [ 1 ]. World Health Organization (WHO) estimates that at least 650 million people worldwide are obese and these numbers steadily increased as they more than doubled between 2000 and 2016 [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Pathways Involved in Formation of Spontaneous and Lipopolysaccharide-Induced Neutrophil Extracellular Traps (NETs) Differ in Obesity and Systemic Inflammation

Cichoń

Ortmann

Kołaczkowska

2021

IJMS

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Obesity manifests itself with low-grade chronic inflammation that shapes immune responses during infection. Albeit obese individuals are at risk of higher mortality due to comorbidities, they are better protected from systemic inflammation. Recently, we showed that in the vasculature of obese mice kept on high-fat diet (HFD), neutrophils produce less neutrophil extracellular traps (NETs) than in lean controls (normal diet, ND). NETs are used by neutrophils to counteract severe infection, but they also cause collateral damage. Hardly anything is known about metabolic requirements for their formation, especially in the context of obesity and/or sepsis. Thus, we aimed to study the immunometabolism of NET formation by application of ex vivo neutrophil analyses (Seahorse analyzer, selective inhibitors, confocal imaging) and intravital microscopy. The obtained data show that glycolysis and/or pentose phosphate pathway are involved in NETs release by ND neutrophils in both physiological and inflammatory conditions. In contrast, such cells of septic HFD mice utilize these routes only to spontaneously cast NETs, while after secondary ex vivo activation they exhibit so called “exhausted phenotype”, which manifests itself in diminished NET release despite high glycolytic potential and flexibility to oxidize fatty acids. Moreover, impact of ATP synthase inhibition on NET formation is revealed. Overall, the study shows that the neutrophil potential to cast NETs depends on both the metabolic and inflammatory state of the individual.

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Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care

Cited by 122 publications

References 127 publications

Obesity-instructed TREM2^high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

Obesity-instructed TREM2^high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

The Role of AMPK Signaling in Brown Adipose Tissue Activation

Metabolic Pathways Involved in Formation of Spontaneous and Lipopolysaccharide-Induced Neutrophil Extracellular Traps (NETs) Differ in Obesity and Systemic Inflammation

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Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care

Cited by 122 publications

References 127 publications

Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

The Role of AMPK Signaling in Brown Adipose Tissue Activation

Metabolic Pathways Involved in Formation of Spontaneous and Lipopolysaccharide-Induced Neutrophil Extracellular Traps (NETs) Differ in Obesity and Systemic Inflammation

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Resources

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Obesity-instructed TREM2^high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

Obesity-instructed TREM2^high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution