Leptin: Less Is More Zhao, Shangang; Kusminski, Christine M; Elmquist, Joel K ...
Diabetes,
05/2020, Letnik:
69, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The successful use of leptin for the treatment of individuals with lipodystrophy and leptin deficiency is well established. However, pharmacological approaches of leptin therapy for the treatment of ...diet-induced obesity have been ineffective. There is ample room for a better understanding of the much famed "leptin resistance" phenomenon. Our recent data in this area prompt us to call for a conceptual shift. This shift entails a model in which a reduction of bioactive leptin levels in the context of obesity triggers a high degree of leptin sensitization and improved leptin action, both centrally and peripherally. Put another way, hyperleptinemia per se causes leptin resistance and associated metabolic disorders. In this perspective, we briefly discuss the underlying conceptual steps that led us to explore partial leptin reduction as a viable therapeutic avenue. We hope this discussion will contribute to potential future applications of partial leptin reduction therapy for the treatment of obesity and type 2 diabetes.
Functional adipose tissue is essential for homeostatic maintenance of systemic metabolism. As such, adipose tissue dysfunction, like that seen in the obese state, directly contributes to system-wide ...pathological metabolism, leading to the development of type 2 diabetes and other obesity-associated comorbidities. In addition to the storage function of adipocytes, they also secrete numerous factors that robustly regulate metabolism-related pathways throughout the body. Many of these factors, in addition to other signaling proteins, RNA species and lipids, are found in extracellular vesicles (EVs) released from adipocytes. EVs are vesicles with a lipid bilayer, known to carry signaling proteins and lipids, mRNAs and miRNAs. Because of this diverse cargo, EVs can have robust and pleotropic signaling effects depending on the receiving target cells. We are only now starting to understand how adipocyte EVs can modulate metabolism within adipose tissue and beyond. Here, we highlight the current literature that demonstrates EV-mediated crosstalk between adipocytes and other tissues or distal cells. We become increasingly aware of the importance of these adipocyte-derived EV signals that establish a so far underappreciated endocrine system. Adipocyte EVs offer a new avenue for pharmacological manipulation of metabolism to treat obesity-related disease.
Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a ...reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.
The prevalence of obesity has increased dramatically in recent decades, reaching epidemic proportions. It is becoming clear that obesity is associated not only with type 2 diabetes mellitus and ...cardiovascular disease, but also with multiple types of cancer. Obesity is characterized by impaired adipose tissue function, leading to adipocyte hypertrophy, inflammation, hypoxia and induced angiogenesis, extracellular matrix remodeling and fibrosis as well as additional stress responses. While epidemiological data indicate that obesity is a well-established risk factor for certain malignancies, the molecular mechanisms underlying the link between obesity and cancer are still poorly understood. Recent data implicates systemic and paracrine factors secreted from adipose tissue during the obese state, promoting cancer development and progression. Here, we focus on the obesity-associated adipose tissue remodeling that may not only lead to metabolic complications, but also to a permissive pro-tumorigenic environment. Particular attention is given to the local pro-tumorigenic effects derived from adipocytes that present an important part of the tumor microenvironment of at least some cancers, in an attempt to describe the nature of the major players of the adipocyte-cancer cell crosstalk that dictates to a large extent tumor progression.
The endocrine functions of the adipose organ are widely studied at this stage. The adipose organ, and in particular adipocytes, communicate with almost all other organs. Although some adipose tissue ...pads assume the functions as distinct “miniorgans,” adipocytes can also be present in smaller numbers interspersed with other cell types. Although fat pads have the potential to have a significant systemic impact, adipocytes may also affect neighboring tissues through paracrine interactions. These local or systemic effects are mediated through lipid and protein factors. The protein factors are commonly referred to as adipokines. Their expression and posttranslational modifications can undergo dramatic changes under different metabolic conditions.
Due to the fact that none of the mutations that affect adipose tissue trigger embryonic lethality, the study of adipose tissue physiology lends itself to genetic analysis in mice. In fact, life in the complete absence of adipose tissue is possible in a laboratory setting, making even the most extreme adipose tissue phenotypes genetically amenable to be analyzed by disruption of specific genes or overexpression of others.
Here, we briefly discuss some basic aspects of adipocyte physiology and the systemic impact of adipocyte-derived factors on energy homeostasis.
The past few years have provided substantial evidence for the vital role of the local tumor microenvironment for various aspects of tumor progression. With obesity and its pathophysiological sequelae ...still on the rise, the adipocyte is increasingly moving center stage in the context of tumor stroma-related studies. To date, we have limited insight into how the systemic metabolic changes associated with obesity and the concomitant modification of the paracrine and endocrine panel of stromal adipocyte-derived secretory products (“adipokines”) influence the incidence and progression of obesity-related cancers. Here, we discuss the role of adipocyte dysfunction associated with obesity and its potential impact on cancer biology.
The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged ...which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as
(PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.
Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to obesity-associated vasculopathy and cardiovascular risk. Circulating ...mediators of inflammation participate in the mechanisms of vascular insult and atheromatous change, and many of these inflammatory proteins are secreted directly from adipocytes and adipose tissue-derived macrophages. Several factors linking obesity with an increased cardiovascular risk have been identified. The adipocyte-specific secretory protein adiponectin is a particularly promising candidate in this context. Its levels are decreased in obesity. Adiponectin may mediate some of its demonstrated cardioprotective effects through its anti-inflammatory properties. In addition to decreased expression of beneficial adipokines, secretion of a host of inflammatory factors from visceral adipose tissue may contribute to the increased cardiovascular risk associated with obesity. The cardioprotective effects of many of the most popular drug regimens corroborate these conclusions, demonstrating that along with improvements in other therapeutic end points, they mediate improvements in systemic inflammation. In some cases, these improvements are attributable to direct suppression of inflammatory signaling in adipocytes. The targeted suppression of various proinflammatory cascades in adipocytes specifically represents an exciting new therapeutic opportunity for the cardiovascular disease area.
Activated beige adipocytes have therapeutic potential due to their ability to improve glucose and lipid homeostasis. To date, the origin of beige adipocytes remains enigmatic. Whether beige cells ...arise through de novo differentiation from resident precursors or through reprogramming of mature white adipocytes has been a topic of intense discussion. Here, we offer our perspective on the natural origin of beige adipocytes in mice. In particular, we revisit recent lineage-tracing studies that shed light on this issue and offer new insight into how environmental housing temperatures early in life influence the mode of beige adipocyte biogenesis upon cold exposure later in life. We suggest a unified model in which beige adipocytes (UCP1
multilocular cells) in rodents initially arise predominantly from progenitors (i.e., de novo beige adipogenesis) upon the first exposure to cold temperatures and then interconvert between "dormant beige" and "active beige" phenotypes (i.e., beige cell activation) upon subsequent changes in environmental temperature. Importantly, we highlight experimental considerations needed to visualize de novo adipogenesis versus beige cell activation in mice. A precise understanding of the cellular origins of beige adipocytes emanating in response to physiological and pharmacological stimuli may better inform therapeutic strategies to recruit beige adipocytes in vivo.
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