IL-25 increases production of beige fat to burn more cellular energy

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An immune signal promotes the production of energy-burning “beige fat,” according to a new study publishing August 5th in the open-access journal PLOS Biology by Zhonghan Yang of Sun Yat-Sen University, Guangzhou, China, and colleagues. The finding may lead to new ways to reduce obesity and treat metabolic disorders.

The beige color in beige fat comes from its high concentration of mitochondria, the cell’s powerhouses.

Mitochondria burn high-energy molecules like fats and sugars with oxygen, releasing energy. Normally, that energy is stored as ATP, the energy currency that the cell uses for almost all its activities. But in beige fat, mitochondria accumulate a protein called “uncoupling protein-1” that limits ATP production, generating heat instead.

Babies are born with “brown fat,” a similar tissue concentrated in the shoulder region, which helps them stay warm, but brown fat is gradually lost with age. Not so beige fat, which is more widely distributed and which can be generated throughout life in response to both cold and neuronal or hormonal stimulation.

Recent work, including by the authors of the new study, has revealed that cytokines—immune system signaling molecules—play a role in regulation of beige fat.

To explore that regulation further, the authors manipulated levels of the cytokine interleukin-25, and showed that an increase in the cytokine could mimic the effects of both cold and stimulation of a hormone receptor in increasing the production of beige fat in mice.

They traced the signaling chain further, showing that IL-25 exerted its effects through two other cytokines, which in turn regulated immune cells called macrophages.

Those cells acted on neurons that terminate in the beige fat tissue, promoting an increase in production of the neurotransmitter norepinephrine, which was already known to promote beige fat production. Thus, the authors’ work revealed the sequence of regulatory signals that begins with IL-25 and ends with release of norepinephrine and an increase in beige fat.

Finally, the authors showed that administering IL-25 to mice that were eating a high-fat diet prevented them from becoming obese and improved their ability to maintain their responsiveness to insulin, which is impaired in chronic obesity.

“Our results show that interleukin-25 plays a key role in production of beige fat,” Yang said, “and point toward increasing interleukin-25 signaling as a potential treatment for obesity.”


The obesity epidemic is worsening worldwide, particularly among youths and young adults [1].Consequently, serious challenges will impact the health care systems in the near future: A progressively earlier onset of obesity associated chronic diseases such as type 2 diabetes mellitus (T2DM), fatty liver, cardiovascular and chronic kidney disease, as well as neurodegenerative disorders and cancer; and a proportional increase in the morbidity load into middle age [2].

Decades of research ground the notion that localized immune cell infiltration in white adipose tissue (WAT), driven by the energy-surplus in obesity, promotes a low grade systemic inflammation which in turn induces a global impairment of insulin action. Metabolic derangements related to obesity are largely mediated by insulin resistance (IR), which greatly increases the risk of T2DM and the burden of its co-morbidities [3,4].

Nevertheless, there might be some beneficial effects of WAT-related immune responses. As in other major metabolic organs, inflammation and inflammatory mediators generated by resident immune cell populations and stromal cells, play essential roles in the maintenance of tissue integrity by stimulating its healthy expansion, remodelling and even repair [4,5,6]. Immune surveillance also extends to local energy and nutrient availability, thereby influencing the metabolic and endocrine performance of adipocytes to meet the metabolic needs derived from over nutrition [4].

Increased adipocyte secretion of various hormones, such as leptin, triggers a brain feed-back-loop that reduces food intake and activates sympathetic nervous system (SNS). This acute adaptive mechanism counteracts the anabolic pressure of increased insulin secretion through increases in the rate of lipolysis and thermogenic processes [5].

However, resolution is needed and during conditions of sustained positive energy balance, this otherwise physiological response, is perpetuated and become pathogenic. Altered production of several cytokines, adipokines and lipid species, as well as activation of multiple immune receptors and intracellular mediators, have been associated with insulin and catecholamine resistance leading to overall metabolic disruption [5,7,8,9,10].

However, metabolic homeostasis still requires an active immune system, since WAT disruption of inflammatory pathways leads to adipocyte dysfunction, dysbiosis and chronic systemic inflammation, as seen in obesity [4,11]. Thus, duration and magnitude of immune responses are key outcome determinants. In line, many so-called pro and anti-inflammatory molecules have been shown to exert contradictory dose and time dependent actions, also influenced by their production and target sites [4]. This also seems to be the case of the classical brown (BAT) and recently discovered beige adipose tissues [12].

In response to cold, brown and, to a lesser extent, beige adipose cells (also called “brite” adipocytes), have the capacity to burn fat or glucose to release energy in the form of heat, in a process called non-shivering thermogenesis (NST) [13]. Their somewhat shared morphological and functional properties are mainly related to the presence of multilocular lipid droplets and a high content of mitochondria expressing uncoupling protein 1 (UCP1) [14].

Recruitment of beige adipocytes in rodent WAT—also termed “WAT browning” or “beiging”—is an adaptive and reversible response to environmental stimuli including: chronic cold acclimation, exercise and nutritional challenges; as well as external and internal cues such as: pharmacological treatment with β3-adrenergic receptor (AR) agonists or thiazolidinediones (TZDs) and various peptides and hormones [12,15].

Indeed, both white and brown fat pads also contain innate immune cells, including M2-like macrophages, eosinophils and innate lymphoid type 2 cells (ILC2s), acting as positive actors in the control of BAT thermogenic activity and WAT browning. Though not exempt of controversies, recent research suggests that a balanced Type 2/Type 1 inflammatory response is essential to maintain the integrity and hormonal sensitivity of brown and beige adipocytes or their precursor cells and regulate sympathetic innervation of thermogenic adipose tissue (AT) [12,16,17,18].

Despite initial controversies about prevalence of BAT in adult humans [19,20], cumulative evidence supports its relevance and the existence of inducible beige-like thermogenic adipocytes that significantly contribute to the regulation of systemic energy homeostasis [13,21]. Constitutive BAT activity is inversely correlated with adiposity, blood glucose concentrations and insulin sensitivity [21,22].

Meanwhile, chronic cold acclimation promotes the recruitment of new thermogenic fat even in subjects with undetectable levels of pre-existing BAT, as proven by Positron Emission Tomography/Computerized Tomography (PET/CT) studies [23,24,25,26]. Interestingly, a substantial proportion of adult BAT located in the neck and supraclavicular region shows a gene expression pattern selective to mouse beige adipocytes [27]; while the deep neck regions resemble classical brown fat in mice [13,28].

Cold inducible-BAT activity correlates with increases in NST and/or an improvement in insulin sensitivity [24,25]. Thereby, fat browning has gained considerable attention due to is potential as a new therapeutic target in the treatment of obesity and its metabolic co-morbidities.

However, this conclusion should be viewed with caution since detrimental effects linked to overactive browning activity have been recently identified as main pathogenic substrate in inflammatory hypermetabolic conditions, such as cancer cachexia and burn injury [29,30,31].

This review aims to summarize and discuss evidence from genetic and pharmacological interventions in rodents (Table 1), as well as human studies reporting beneficial or deleterious effects of various cytokines on energy expenditure (EE) through beige and brown fat activation. Besides local actions, we will draw attention to their influence in the central nervous system (CNS) networks governing, through hypothalamic mediated SNS efferences, the thermoregulatory and metabolically driven alterations in BAT and beige thermogenesis.

Table 1 – Summary of cellular transfer, transgenic or pharmacological approaches targeting cytokine signalling with effects on BAT activity and beige fat recruitment.

ReferenceInterventional ApproachCell/Cytokine/Intracellular MediatorRodent Model (Genetic Background)Age (week)External Cue
(T °C, Diet, Treatment)
GenderEffects on EE, Thermogenesis and Metabolic Homeostasis
Nguyen, 2011Global knockoutIL4/IL13
STAT6
BALB/cJ
BALB/cJ or C5BL6J
8–124 °C, 6 hmaleDecreased weight loss
Cold-induced hypothermia
Decreased BAT thermogenic gene expression
Exhausted lipid stores in BAT
Decreased serum FFA
Blunted M2-like markers in BAT and WAT
Conditional knockout, myeloid-specificIL4RABALB/cJ
IL4RαL/LLysMCre
Global knockoutIL4/IL13BALB/cJ4 °C, 6 h Acute β3-agonist treatmentNormalized weight loss
Increased EE
Increased core body temperature
Increased thermogenic gene expression
Increased lipid storage in BAT
Global deletion, clodronate liposomes treatmentMacrophages4 °C, 6 hCold-induced hypothermia
Decreased BAT thermogenic gene expression
Blunted M2-like markers in BAT and WAT
Qiu, 2014Global knockoutIL4/IL13
STAT6
IL4RA
BALB/cJ124 °C, 48 hmaleDecreased cold induced EE (VO2) (STAT6 and IL4RA KO)
Cold-induced hypothermia
Impaired browning
Reduced sc WAT thermogenic gene expression
Decreased scWAT oxygen consumption
(IL4/IL13 KO)
Eosinophil deficient 4get/ΔdblGata miceEosinophilsDecreased cold induced EE (VO2)
Impaired browning
Reduced sc WAT thermogenic gene expression
Global knockoutCCR2Decreased cold-induced ATM recruitment
Decreased cold induced EE (VO2)
Impaired browning
Reduced sc WAT thermogenic gene expression
IL4 i.p. treatment (IL4 complexed)DIO C57BL6/JHFD 10 weeks
30 °C
IL4 treatment 14 days
Decreased body weight
Decreased fat mass
Improved insulin sensitivity
Increased browning
Brestoff, 2015Global knockoutIL33C57BL6/J7LFD 12 weeksmaleIncreased body weight
Increased fat mass
Insulin resistance
Decreased beige adipocytes in scWAT
Decreased ILC2s content in scWAT
IL33 i.p. treatment8LFD 12 weeks
IL33 treatment
7 days
Decreased fat mass
Increased EE
Increased browning in scWAT
HFD and
IL33 treatment
4 weeks
Counteracts DIO
Abrogates glucose intolerance
Increases ILC2s and Treg content in WAT
adoptively transferred congenic ILC2ILC2-deficient Rag
2 mice
IL33 treatment 7 daysIncreased UCP1 protein in iWAT
Increased iWAT browning dependent on ILC2s
Lee, 2015IL33 i.p. treatment
IL13 i.p. treatment
IL4 i.p. treatment
C57BL6/J or IL5Red5/+, R5
BALB/cJ
8–12Cytokine treatment 8 days
30 °C
maleIncreased browning of scWAT
Elicited beige progenitors (IL33, R5 mice)
Increased scWAT UCP1 protein levels
Increase cold-induced EE (IL33 treatment)
Global knockoutIL5 (eosinophil growth factor)
Normal IL13 secretion
IL5Red5/Red5
BALB/cJ
IL33 treatment 8 days
30 °C
Elicited proliferation of beige progenitors
IL4/IL13
IL4RA
BALB/cJFailed to increase proliferation of beige progenitors
IL4 i.p. treatment
(IL4 complexed)
C57BL6/J30 °C
IL4 treatment, 24–48 h
Elicited proliferation of beige progenitors
Conditional knockout, Progenitor cells specificIL4RAIL4RAf/fPdgfraCreFailed to increase proliferation of beige progenitors
Odegaard, 2016Global knockoutIL33
IL1R1 (ST2)
Adult: 8–12
Perinatal: 3–4
5 °C 48 hmale and femaleImpaired cold-induced iWAT UCP1 expression
Impaired browning
Decreased survival in cold
Fisher, 2017IL4 i.p. treatment Global knockoutNone
IL4RA
C57BL6/J12Daily treatment 14 days
Declining T-30–5 °C
maleUnchanged body weight and EE
No activation of thermogenic gene program in iWAT
Ding, 2016IL33 i.p. treatmentC57BL6/J6HFD 11 weeks
IL33 treatment 7 days
maleRestoration of ILC2s and eosinophils content in scWAT
Increased UCP1 protein level in scWAT
ST2 antibody treatment7ST2 antibody treatment 4 °C 48 hBlunted ILC2s and eosinophils recruitment
Decreased UCP1 protein levels in WAT
Wallenius, 2002IL6 icv administrationSprague-Dawley ratsAcute IL6 treatmentmaleIncreased EE (VO2)
Lowers body weight and fat mass
Unchanged food intake and activity
Wernstedt, 2003
Wallenius, 2002
Global knockoutIL6C57BL6/J8Cold challenge (6 h 4 °C)
Stress challenge (1 h)
maleSpontaneous mature onset obesity
Decreased EE in cold and stress
Lower body core temperature
Decreased NE serum levels
Li, 2002Adenoviral IL6 gene delivery icvIL6Sprague-Dawley rats5 weeksmaleSupressed weight gain and adiposity
Increased BAT UCP1 protein levels
Blunted by denervation of BAT
Knudsen, 2014Global knockoutIL6C57BL6/J8Treadmill running 5 weeks or 4 °C, 3 daysmaleReduced sc WAT browning and UCP1 levels
Partially reversed by IL6 treatment
IL6 i.p. treatmentC57BL6/J7 daysmaleIncreased sc WAT UCP1 levels
Petruzzelli,2014Transgenic mice with epithelial cell specific overexpression (cancer cachexia)SOS-FK5-SOS
(skin tumours)
C57BL6/J
5Anti-IL6 Ab
BAT denervation
Loss of body weight
Fat and muscle wasting
Increased UCP1 in sc WAT
Increased EE
Effects blunted by blocking IL6 or denervation
Patsouris, 2015Global knockout
Burn mice
IL6C57BL6/JBurn back by 98 °C for 10 s
Evaluation 2 days post-burn
Increase scWAT browning in WT
Increased scWAT UCP1 levels
Effects blunted in IL6KO mice
Effects blunted after propranolol treatment
Almendro, 2008IL15 i.p. treatmentWistar ratsDaily administration for 7 daysmaleDecreased WAT and BAT mass
Increased BAT UCP1 gene expression
Increased expression of FA oxidation genes
Sun, 2016Hydrodynamic gene delivery
Untargeted overexpression
IL15:IL15ADIO C57BL6/J610 weeks
Administration every 10 days
maleReduced body weight
Reduced adiposity
Increased thermogenic markers in BAT and iWAT
Improved insulin sensitivity
Lacraz, 2016Global knockoutIL15C57BL6/J416 weeks on HFD or 10 °C, 20 h or β3-agonist treatmentmaleResistance to DIO and IR
Higher EE than controls
Increased expression of genes associated with thermogenesis
Elevated basal core temperature
Increased BAT activation and iWAT browning in response to cold
Pazos, 2015Global knockoutIL18C57BL6/J810 weeks of HFD
4 °C 6 h
4 °C 5 days
maleHFD obesity prone
Decreased UCP1 expression in BAT and iWAT
Hypothermic after short cold challenge
Null browning of scWAT in response to cold
IL18R1C57BL6/J10 weeks of HFD
Acute HFD challenge
4 °C 6 h
4 °C 5 days
DIO resistant
Increased UCP1 expression in sc WAT
Increased EE in response to HFD challenge
Maintenance of body temperature in cold
Increased browning of scWAT and activation of thermogenic program

BAT: brown adipose tissue; FFA: free fatty acid; WAT: white adipose tissue; EE: energy expenditure; DIO: diet induced obesity; UCP1: uncoupling protein 1; iWAT: inguinal white adipose tissue; scWAT: subcutaneous WAT; VO2: oxygen consumption; NE: norepinephrine; IR: insulin resistance; HFD: high fat diet; ILC2s: innate lymphoid type 2 cells.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164446/


More information: Li L, Ma L, Zhao Z, Luo S, Gong B, Li J, et al. (2021) IL-25–induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice. PLoS Biol 19(8): e3001348. doi.org/10.1371/journal.pbio.3001348

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