The glucoregulatory actions of leptin

D'souza, Anna M.; Neumann, Ursula; Glavas, Maria M.; Kieffer, Timothy J.

doi:10.1016/j.molmet.2017.04.011

Cited by 150 publications

(129 citation statements)

References 238 publications

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“…matrix metallopeptidase 12, Mmp12; procollagen c-endopeptidase enhancer, Pcolce ) (19,20) and cytokines (e.g. coagulation factor VII, F7; leptin, Lep; secreted frizzled-related protein 1, Sfrp1 ) (21–23). These genes are not differentially expressed in white adipose from the same animals, and they are not differentially expressed in low fat-fed brown or white adipose between 20 and 30 weeks ( Supplemental Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Carson

Macias-Velasco

Gunawardana

et al. 2019

Preprint

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52Disruption of glucose homeostasis increases the risk of type II diabetes, cardiovascular disease, stroke, 53 and cancer. We leverage a novel rodent model, the SM/J mouse, to understand glycemic control in 54 obesity. On a high fat diet, obese SM/J mice initially develop impaired glucose tolerance and elevated 55 fasting glucose. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistence of 56 obesity. A prominent phenotype is that they dramatically expand their brown adipose depots as they 57 resolve glycemic dysfunction. This occurs naturally and spontaneously on a high fat diet, with no 58 temperature or genetic manipulation. When the brown adipose depot is removed from normoglycemic 59 obese mice, fasting blood glucose and glucose tolerance revert to unhealthy levels, and animals become 60 insulin resistant. We identified 267 genes whose expression changes in the brown adipose when the 61 mice resolve their unhealthy glycemic parameters, and find the expanded tissue has a 'healthier' 62 expression profile of cytokines and extracellular matrix genes. We describe morphological, physiological, 63 and transcriptomic changes that occur during the unique brown adipose expansion and remission of 64 glycemic dysfunction in obese SM/J mice. Understanding this phenomenon in mice will open the door for 65 innovative therapies aimed at improving glycemic control in obesity.66 67 Significance Statement 68 Some obese individuals maintain normal glycemic control. Despite being obese, these individuals 69 have low risk for metabolic complications, including type-II diabetes. If we better understood why some 70 obese people maintain normoglycemia then we might develop new approaches for treating metabolic 71 complications associated with obesity. However, the causative factors underlying glycemic control in 72 obesity remain unknown. We discovered that, despite persistence of the obese state, SM/J mice enter 73 into diabetic remission: returning to normoglycemia and reestablishing glucose tolerance and improving 74 insulin sensitivity. A prominent phenotype is that they dramatically expand their brown adipose depots as 75 they resolve glycemic dysfunction. Understanding this phenomenon in mice will open the door for 76 innovative therapies aimed at improving glycemic control in obesity. 78An estimated 10-30% of obese individuals maintain glycemic control and some longitudinal 79 studies suggest their risk of developing type II diabetes is no greater than matched lean individuals (1). 80No causative factors underlying glycemic control in obesity have been discovered, however the strongest 81 predictors of impaired glycemic control in obesity are increased visceral fat mass and adipose tissue 82 dysfunction (2,3). Thus research efforts have focused on understanding the genetic and physiological 83 mechanisms of action of adipose. Recent research reveals that brown adipose activity is associated with 84 anti-diabetic properties. Cold exposure in both obese and lean individuals causes increased uptake...

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Section: Resultsmentioning

confidence: 99%

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Carson

Macias-Velasco

Gunawardana

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…This cluster is mainly characterized by its response to leptin (LEP), which was also identified as one of the main functions of FB6. LEP is a proteohormone secreted by white adipocytes, targeting the hypothalamus and thereby regulating the energy balance of the body . Interestingly, our transcriptome analysis revealed that FB3 and FB6 highly and FB1 to a minor degree express the LEP‐receptor ( LEPR , Figure S15).…”

Section: Discussionmentioning

confidence: 97%

“…LEP is a proteohormone secreted by white adipocytes, targeting the hypothalamus and thereby regulating the energy balance of the body. 55,56 Interestingly, our transcriptome analysis revealed that FB3 and FB6 highly and FB1 to a minor degree express the LEP-receptor (LEPR, Figure S15). Since application of LEP on mouse wounds has been shown to promote wound healing, 57,58 and blocking of LEP delays wound healing, 57 our data suggest a contribution of FB3 and FB6 to wound healing in response to LEP.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

et al. 2020

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Though skin fibroblasts (FB) are the main cell population within the dermis, the different skin FB subsets are not well characterized and the traditional classification into reticular and papillary FBs has little functional relevance. To fill the gap of knowledge on FB diversity in human skin, we performed single‐cell RNA sequencing. Investigation of marker genes for the different skin cell subtypes revealed a heterogeneous picture of FBs. When mapping reticular and papillary FB markers, we could not detect cluster specificity, suggesting that these two populations show a higher transcriptional heterogeneity than expected. This finding was further confirmed by in situ hybridization, showing that DPP4 was expressed in both dermal layers. Our analysis identified six FB clusters with distinct transcriptional signatures. Importantly, we could demonstrate that in human skin DPP4+ FBs are the main producers of factors involved in extracellular matrix (ECM) assembly. In conclusion, we provide evidence that hitherto considered FB markers are not ideal to characterize skin FB subpopulations in single‐cell sequencing analyses. The identification of DPP4+ FBs as the main ECM‐producing cells in human skin will foster the development of anti‐fibrotic treatments for the skin and other organs.

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“…Indeed, if the function of leptin is to stimulate lipolysis, why would leptin levels decrease in situations where lipolysis needs to be activated? One possibility is that the effects of leptin on lipolysis depend on insulin levels 96 and on the sympathetic tone.…”

Section: Leptin and Adipose Functionsmentioning

confidence: 99%

Leptin and brain–adipose crosstalks

et al. 2018

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Interactions between the brain and distinct adipose depots have a key role in maintaining energy balance, thereby promoting survival in response to metabolic challenges such as cold exposure and starvation. Recently, there has been renewed interest in the specific central neuronal circuits that regulate adipose depots. Here, we review anatomical, genetic and pharmacological studies on the neural regulation of adipose function, including lipolysis, non-shivering thermogenesis, browning and leptin secretion. In particular, we emphasize the role of leptin-sensitive neurons and the sympathetic nervous system in modulating the activity of brown, white and beige adipose tissues. We provide an overview of advances in the understanding of the heterogeneity of the brain regulation of adipose tissues and offer a perspective on the challenges and paradoxes that the community is facing regarding the actions of leptin on this system.

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The glucoregulatory actions of leptin

Cited by 150 publications

References 238 publications

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

Leptin and brain–adipose crosstalks

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