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18 pages, 7041 KiB

Open AccessArticle

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

by Jennifer L. Bailey, David H. Burk, Susan J. Burke, Scott D. Reed, Sujoy Ghosh and Carrie M. Elks

Biomedicines 2022, 10(9), 2077; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092077 - 25 Aug 2022

Cited by 1 | Viewed by 1318

Abstract

Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in [...] Read more.

Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in vascular defects that complicate the interpretation of metabolic data. Here, we describe the generation and initial phenotypic analysis of an adipocyte-specific LAMA4 knockout mouse (Lama4^AKO). We first performed an in-silico analysis to determine the degree to which laminin α4 was expressed in human and murine adipocytes. Next, male Lama4^AKO and control mice were fed chow or high-fat diets and glucose tolerance was assessed along with serum insulin and leptin levels. Adipocyte area was measured in both epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively), and eWAT was used for RNA-sequencing. We found that laminin α4 was highly expressed in human and murine adipocytes. Further, chow-fed Lama4^AKO mice are like control mice in terms of body weight, body composition, and glucose tolerance, although they have larger eWAT adipocytes and lower insulin levels. High-fat-fed Lama4^AKO mice are fatter and more glucose tolerant when compared to control mice. Transcriptionally, the eWAT of high-fat fed Lama4^AKO mice resembles that of chow-fed control mice. We conclude from these findings that adipocyte-specific LAMA4 deletion is protective in an obesogenic environment, even though overall adiposity is increased. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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16 pages, 4480 KiB

Open AccessArticle

The Potential Role of Myokines/Hepatokines in the Progression of Neuronal Damage in Streptozotocin and High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice

by Heaji Lee and Yunsook Lim

Biomedicines 2022, 10(7), 1521; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10071521 - 27 Jun 2022

Cited by 6 | Viewed by 2117

Abstract

Background: Diabetes is highly prevalent, and the number of patients with diabetic sarcopenia and cognitive impairment has grown, leading to decreased quality of life. Although the exact mechanisms between sarcopenia and cognitive impairment have not been elucidated, it is speculated that muscle and [...] Read more.

Background: Diabetes is highly prevalent, and the number of patients with diabetic sarcopenia and cognitive impairment has grown, leading to decreased quality of life. Although the exact mechanisms between sarcopenia and cognitive impairment have not been elucidated, it is speculated that muscle and liver-derived mediators might contribute to brain function. This study examined the molecular mechanisms associated with muscle-brain interaction accompanied by insulin resistance (IR) caused by aberrant energy metabolism via myokines/hepatokines in type 2 diabetes mellitus (T2DM) mice. Methods: T2DM was induced by a high-fat diet and streptozotocin injection. Behavior tests were conducted to analyze grip strength and cognitive function. Histopathological changes in skeletal muscle and brain tissue were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to energy metabolism via myokines/hepatokines were measured by western blot. Results: T2DM caused peripheral and central IR. Furthermore, T2DM led to aberrant energy metabolism through the reduced fibroblast growth factor 21 dependent AMP-activated kinase (AMPK)/surtuin1/proliferator-activated receptor γ coactivator-1α pathway in T2DM. Subsequently, reduced circulating myokines/hepatokines were in accordance with their levels with hippocampal neuronal markers in T2DM mice. Accordingly, skeletal muscle (muscle strength: 2.83 ± 0.39 vs. 2.187 ± 0.51, p = 0.004) and brain function (PAT: 38.5 ± 57.91 vs. 11.556 ± 12.03, p = 0.02) impairment and morphological changes (muscle cross-sectional area: 872.43 ± 242.87 vs. 743.68 ± 169.31, p = 0.01; density of neurons in hippocampus: 145 ± 15.13 vs. 77 ± 35.51, p = 0.05; density of neurons in cortex: 138.333 ± 6.66 vs. 78 ± 17.35, p = 0.05) were shown in T2DM mice. In addition, the working ability demonstrated by Y-maze was positively correlated with % lean mass (p = 0.046, R = 0.3426). Conclusions: T2DM led to aberrant energy in skeletal muscle and brain via myokines/hepatokines. This study suggested that myokines and hepatokines might have potential roles in skeletal muscle and central metabolic functions which can mediate cognitive function in T2DM mice. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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20 pages, 1954 KiB

Open AccessArticle

Morbid Obesity in Women Is Associated with an Altered Intestinal Expression of Genes Related to Cancer Risk and Immune, Defensive, and Antimicrobial Response

by Ailec Ho-Plágaro, Cristina Rodríguez-Díaz, Concepción Santiago-Fernández, Carlos López-Gómez, Sara García-Serrano, Flores Martín-Reyes, Francisca Rodríguez-Pacheco, Alberto Rodríguez-Cañete, Guillermo Alcaín-Martínez, Luis Vázquez-Pedreño, Sergio Valdés, Lourdes Garrido-Sánchez and Eduardo García-Fuentes

Biomedicines 2022, 10(5), 1024; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051024 - 29 Apr 2022

Viewed by 1760

Abstract

Background: Little is known about the relation between morbid obesity and duodenal transcriptomic changes. We aimed to identify intestinal genes that may be associated with the development of obesity regardless of the degree of insulin resistance (IR) of patients. Material and Methods: Duodenal [...] Read more.

Background: Little is known about the relation between morbid obesity and duodenal transcriptomic changes. We aimed to identify intestinal genes that may be associated with the development of obesity regardless of the degree of insulin resistance (IR) of patients. Material and Methods: Duodenal samples were assessed by microarray in three groups of women: non-obese women and women with morbid obesity with low and high IR. Results: We identified differentially expressed genes (DEGs) associated with morbid obesity, regardless of IR degree, related to digestion and lipid metabolism, defense response and inflammatory processes, maintenance of the gastrointestinal epithelium, wound healing and homeostasis, and the development of gastrointestinal cancer. However, other DEGs depended on the IR degree. We mainly found an upregulation of genes involved in the response to external organisms, hypoxia, and wound healing functions in women with morbid obesity and low IR. Conclusions: Regardless of the degree of IR, morbid obesity is associated with an altered expression of genes related to intestinal defenses, antimicrobial and immune responses, and gastrointestinal cancer. Our data also suggest a deficient duodenal immune and antimicrobial response in women with high IR. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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Review

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18 pages, 1835 KiB

Open AccessReview

Insulin Resistance and High Blood Pressure: Mechanistic Insight on the Role of the Kidney

by Gabriele Brosolo, Andrea Da Porto, Luca Bulfone, Antonio Vacca, Nicole Bertin, Laura Scandolin, Cristiana Catena and Leonardo A. Sechi

Biomedicines 2022, 10(10), 2374; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102374 - 23 Sep 2022

Cited by 10 | Viewed by 5364

Abstract

The metabolic effects of insulin predominate in skeletal muscle, fat, and liver where the hormone binds to its receptor, thereby priming a series of cell-specific and biochemically diverse intracellular mechanisms. In the presence of a good secretory reserve in the pancreatic islets, a [...] Read more.

The metabolic effects of insulin predominate in skeletal muscle, fat, and liver where the hormone binds to its receptor, thereby priming a series of cell-specific and biochemically diverse intracellular mechanisms. In the presence of a good secretory reserve in the pancreatic islets, a decrease in insulin sensitivity in the metabolic target tissues leads to compensatory hyperinsulinemia. A large body of evidence obtained in clinical and experimental studies indicates that insulin resistance and the related hyperinsulinemia are causally involved in some forms of arterial hypertension. Much of this involvement can be ascribed to the impact of insulin on renal sodium transport, although additional mechanisms might be involved. Solid evidence indicates that insulin causes sodium and water retention, and both endogenous and exogenous hyperinsulinemia have been correlated to increased blood pressure. Although important information was gathered on the cellular mechanisms that are triggered by insulin in metabolic tissues and on their abnormalities, knowledge of the insulin-related mechanisms possibly involved in blood pressure regulation is limited. In this review, we summarize the current understanding of the cellular mechanisms that are involved in the pro-hypertensive actions of insulin, focusing on the contribution of insulin to the renal regulation of sodium balance and body fluids. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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15 pages, 876 KiB

Open AccessReview

The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?

by Céline Saint-Laurent, Laurène Mazeyrie, Mylène Tajan, Romain Paccoud, Isabelle Castan-Laurell, Philippe Valet, Thomas Edouard, Jean-Philippe Pradère, Cédric Dray and Armelle Yart

Biomedicines 2022, 10(9), 2139; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092139 - 31 Aug 2022

Cited by 2 | Viewed by 2127

Abstract

The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose [...] Read more.

The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose homeostasis, pointing out a relationship between its dysfunction and insulin resistance, and the therapeutic potential of its targeting. While studies from cellular or tissue-specific models concluded on both pros-and-cons effects of SHP2 on insulin resistance, recent data from integrated systems argued for an insulin resistance promoting role for SHP2, and therefore a therapeutic benefit of its inhibition. In this review, we will summarize the general knowledge of SHP2’s molecular, cellular, and physiological functions, explaining the pathophysiological impact of its dysfunctions, then discuss its protective or promoting roles in insulin resistance as well as the potency and limitations of its pharmacological modulation. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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18 pages, 1219 KiB

Open AccessReview

Falling Short: The Contribution of Central Insulin Receptors to Gait Dysregulation in Brain Aging

by Sami L. Case, Hilaree N. Frazier, Katie L. Anderson, Ruei-Lung Lin and Olivier Thibault

Biomedicines 2022, 10(8), 1923; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10081923 - 09 Aug 2022

Cited by 3 | Viewed by 2742

Abstract

Insulin resistance, which manifests as a reduction of insulin receptor signaling, is known to correlate with pathological changes in peripheral tissues as well as in the brain. Central insulin resistance has been associated with impaired cognitive performance, decreased neuronal health, and reduced brain [...] Read more.

Insulin resistance, which manifests as a reduction of insulin receptor signaling, is known to correlate with pathological changes in peripheral tissues as well as in the brain. Central insulin resistance has been associated with impaired cognitive performance, decreased neuronal health, and reduced brain metabolism; however, the mechanisms underlying central insulin resistance and its impact on brain regions outside of those associated with cognition remain unclear. Falls are a leading cause of both fatal and non-fatal injuries in the older population. Despite this, there is a paucity of work focused on age-dependent alterations in brain regions associated with ambulatory control or potential therapeutic approaches to target these processes. Here, we discuss age-dependent alterations in central modalities that may contribute to gait dysregulation, summarize current data supporting the role of insulin signaling in the brain, and highlight key findings that suggest insulin receptor sensitivity may be preserved in the aged brain. Finally, we present novel results showing that administration of insulin to the somatosensory cortex of aged animals can alter neuronal communication, cerebral blood flow, and the motivation to ambulate, emphasizing the need for further investigations of intranasal insulin as a clinical management strategy in the older population. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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27 pages, 2091 KiB

Open AccessReview

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

by Elizabeth M. Rhea, William A. Banks and Jacob Raber

Biomedicines 2022, 10(7), 1582; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10071582 - 02 Jul 2022

Cited by 16 | Viewed by 6784

Abstract

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, [...] Read more.

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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17 pages, 1355 KiB

Open AccessReview

Mitochondrial Phenotype as a Driver of the Racial Dichotomy in Obesity and Insulin Resistance

by Filip Jevtovic, Polina M. Krassovskaia, Christian A. Lopez, Kelsey H. Fisher-Wellman, Ronald N. Cortright and Nicholas T. Broskey

Biomedicines 2022, 10(6), 1456; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061456 - 20 Jun 2022

Cited by 2 | Viewed by 2383

Abstract

African Americans (AA) are disproportionately burdened by metabolic diseases. While largely unexplored between Caucasian (C) and AA, differences in mitochondrial bioenergetics may provide crucial insight to mechanisms for increased susceptibility to metabolic diseases. AA display lower total energy expenditure and resting metabolic rate [...] Read more.

African Americans (AA) are disproportionately burdened by metabolic diseases. While largely unexplored between Caucasian (C) and AA, differences in mitochondrial bioenergetics may provide crucial insight to mechanisms for increased susceptibility to metabolic diseases. AA display lower total energy expenditure and resting metabolic rate compared to C, but paradoxically have a higher amount of skeletal muscle mass, suggestive of inherent energetic efficiency differences between these races. Such adaptations would increase the chances of overnutrition in AA; however, these disparities would not explain the racial difference in insulin resistance (IR) in healthy subjects. Hallmarks associated with insulin resistance (IR), such as reduced mitochondrial oxidative capacity and metabolic inflexibility are present even in healthy AA without a metabolic disease. These adaptations might be influential of mitochondrial “substrate preference” and could play a role in disproportionate IR rates among races. A higher glycolytic flux and provision of shuttles transferring electrons from cytosol to mitochondrial matrix could be a contributing factor in development of IR via heightened reactive oxygen species (ROS) production. This review highlights the above concepts and provides suggestions for future studies that could help delineate molecular premises behind potential impairments in insulin signaling and metabolic disease susceptibility in AA. Full article

(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)

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