IL-15 Overexpression Promotes Endurance, Oxidative Energy Metabolism, and Muscle PPARδ, SIRT1, PGC-1α, and PGC-1β Expression in Male Mice

Quinn, LeBris S.; Anderson, Bárbara; Conner, Jennifer D.; Wolden‐Hanson, Tami

doi:10.1210/en.2012-1773

Cited by 91 publications

(97 citation statements)

References 42 publications

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“…Metabolic parameters, physical activity, and food intake were measured using a comprehensive laboratory animal monitoring system (CLAMS; Columbus Instruments, Columbus, OH) as previously described [28]. Male CD-1 mice were monitored for 48 h in individual cages, with a 12 h light/dark cycle at thermoneutrality (30°C).…”

Section: Methodsmentioning

confidence: 99%

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Salameh

Bullock

Hujoel

et al. 2015

JAD

Self Cite

108

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Intranasal insulin has shown effficacy in patients with Alzheimer’s disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory defficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

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Section: Methodsmentioning

confidence: 99%

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Salameh

Bullock

Hujoel

et al. 2015

JAD

Self Cite

108

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“…IL-15 gene promoter contains a NF-κB response element that induces IL-15 transcription upon NF-κB activation [21,22]. IL-15 expression in muscle myotubes is induced by treadmill running in healthy individuals [23], in which IL-15 may promote endurance and fuel supply as suggested by a study of muscle in mice [24]. IL-15 expression in muscle is likely regulated by growth hormone.…”

Section: Il-15mentioning

confidence: 99%

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

2014

Front. Med.

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In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the pro-inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

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“…Oversecretion of IL-15 from muscle is associated with reduced adiposity, resistance to DIO, and improved insulin sensitivity (38,39), suggesting that IL-15 can function as myokine (i.e., molecules secreted by the muscle and able to mediate effects on different tissues) (32,44). Interestingly, mice lacking IL-15R␣ and mice overexpressing IL-15 share some common features like increased muscle oxidative capacity and fatigue resistance (33,34,37,28).IL-15R␣ does not have intrinsic kinase activity; therefore, its primary biological function is to bind IL-15 and allow its transpresentation to cells expressing IL-2/15R␤ and ␥ c (46). A shed form of IL-15R␣ is also present in the bloodstream where it binds and increases the half-life of 25).…”

mentioning

confidence: 99%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...

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IL-15 Overexpression Promotes Endurance, Oxidative Energy Metabolism, and Muscle PPARδ, SIRT1, PGC-1α, and PGC-1β Expression in Male Mice

Cited by 91 publications

References 42 publications

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

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