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

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.

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