Beige fat provide protection from dementia

Beige is considered a calming paint color, and scientists have new evidence that beige fat has a similar impact on the brain, bringing down the inflammation associated with the more common white fat and providing protection from dementia.

They have found that beige fat cells, which are typically intermingled with white fat cells in the subcutaneous fat present on “pear shaped” people, mediate subcutaneous fat’s brain protection, Dr. Alexis M. Stranahan and her colleagues report in the journal Nature Communications.

Pear-shaped people, whose weight is generally distributed more evenly, rather than “apple shaped” individuals with fat clustered around their middle and often around internal organs like the liver in the abdominal cavity, are considered less at risk for cardiometabolic problems like heart disease and diabetes, as well as cognitive decline, says Stranahan, neuroscientist at the Medical College of Georgia at Augusta University.

Now the scientists have shown that beige fat cells, or adipocytes, are “indispensable” to the neuroprotective and anti-inflammatory effects of subcutaneous fat, says Stranahan, the study’s corresponding author.

In fact without beige adipocytes, in the face of a high-fat diet, they saw subcutaneous fat start acting more like dangerous visceral fat, says Stranahan who reported last year in The Journal of Clinical Investigation that visceral adiposity sends a message to resident immune cells in the brain to fire up the inflammation, which ultimately damages cognition. “It’s a very different signature,” she says.

Visceral fat around the organs is mostly white fat cells, which store energy as triglycerides, which are yet another fat type found in the blood, and a risk factor for heart disease and stroke at high levels. Particularly in younger people, subcutaneous fat is a mixture of white and beige fat cells, and these beige cells are more like brown fat cells, which are packed with powerhouses called mitochondria and are efficient at using fat and sugars to produce heat in a process called thermogenesis.

Exercise and cold exposure are said to enable the so-called “beiging” of white fat cells.

For some of their studies, the scientists used male mice with a specific gene knocked out that prevents adipocytes in the subcutaneous fat from beiging or browning, effectively resulting in subcutaneous fat that is more like visceral fat.

On a high-fat diet, it’s already been shown that these mice develop diabetes more rapidly than those with normal amounts of beige fat.

It’s also known that transplanting subcutaneous fat into an obese mouse will improve their metabolic profile in a few weeks, and she wanted to know about potential impact on cognitive problems.

While both the normal and knockout mice gained about the same amount of weight over four weeks, mice without functional beige fat displayed accelerated cognitive dysfunction on testing, and their brains and bodies indicated a strong, rapid inflammatory response to the high-fat diet that included activation of microglial cells, those resident immune cells in the brain, which can further heighten inflammation and contribute to dementia and other brain problems.

Before they ever developed diabetes, the microglia of the mice, whose ages were comparable to a 20-something-year-old, had already turned on numerous inflammatory markers. Interestingly normal mice they studied as controls also turned on these markers but turned on anti-inflammatory markers as well apparently to minimize any response.

Normally it takes mice about three months on a high-fat diet to show the kind of responses they saw in the beige-fat knockouts in a single month.

To further explore the impact of beige fat, they also transplanted subcutaneous fat from young, lean healthy mice into the visceral compartment of otherwise normal but now-obese mice who had developed dementia-like behavior after remaining on a high-fat diet for 10 to 12 weeks.

Transplanting the subcutaneous fat resulted in improved memory, restoring essentially normal synaptic plasticity – the ability of the connections between neurons to adapt so they can communicate – in the hippocampus, the center of learning and memory deep in the brain.

These positive changes were dependent on the beige adipocytes in the donor subcutaneous fat, Stranahan and her colleagues write.

Transplants from the beige-fat knockouts on the other hand did not improve cognition in the obese mice, including by strictly objective measures like any increased electrical activity between neurons.

“If we can figure out what it is about beige fat that limits inflammation and maybe what it is about beige fat that improves brain plasticity, then maybe we can mimic that somehow with a drug or with cold-stimulated beiging or even taking out some of your subcutaneous fat when you are young, freezing it and giving it back to you when you are older,” Stranahan says.

All fat tends to be packed with immune cells, which can both promote and calm inflammation. They found beige fat interacts continuously with those immune cells, inducing the anti-inflammatory cytokine IL-4 in the subcutaneous fat. IL-4 in turn is required for cold to stimulate the “beiging” of fat, she notes.

Also in turn, the fat induced IL-4 in microglia and T cells, key drivers of the immune response, in the meninges, a sort of multilayer cap that fits over the brain to help protect it. They also found T cells in the choroid plexus, where cerebrospinal fluid is produced, had calming IL-4 induced.

Their findings suggest IL-4 is directly involved in communication between beige adipocytes and neurons in the hippocampus, the scientists write.

“It’s kind of like “Whisper Down the Lane” if you ever played that at camp,” Stranahan says of what appears to be a calming chain of communication.

When Stranahan and her team looked further they found it was the recipient’s own T cells in the meninges that were called to positive, protective action by the transplanted beige fat cells, not immune cells from the transplanted fat itself.

There is evidence that in chronic obesity, your own immune cells can reach the brain, and there was no evidence in this case that it was the donor’s immune cells making the journey.

“It’s exciting because we have a way for peripheral immune cells to interact with the brain in a way that promotes cognition,” Stranahan says, noting that there also are many bad things immune cells could do in the brain like contribute to stroke and Alzheimer’s.

Her many next goals include learning more about how much it matters where you put the transplanted fat, like whether transferring subcutaneous fat to a subcutaneous area might work even better to protect against cognitive decline; whether transplanting visceral fat to a subcutaneous area decreases its damaging effect; and better understanding how subcutaneous fat sends what appears to be an active anti-inflammatory message. She also wants to explore these issues in female mice since the current studies were limited to males.

But what they and others already are finding underscores the importance of inherent fat distribution, which could be a biomarker for those most at risk for cognitive decline, she says.

The stage of obesity may be another factor, because she also has early evidence suggesting that the longer a high-fat diet is maintained and the more subcutaneous fat increases, its protective powers decrease and visceral fat increases.

Even in a healthy, non-obese young person visceral fat is going to produce higher levels of basal inflammation, Stranahan notes.

Stranahan emphasizes that she does not want her findings to cause excessive concern in overweight individuals or generate more prejudice against them, rather the work is about better identifying risk factors and different points and methods of intervention to fit the needs of individuals.

Stranahan and her colleagues reported in 2015 in the journal Brain, Behavior, and Immunity that a high-fat diet prompts microglia to become uncharacteristically sedentary and to start eating the connections between neurons.

In adults, brown fat is primarily located between the shoulder blades and in the upper chest. Evidence suggests we can increase brown and beige fat cells by exposing ourselves to cooler to cold temperatures for several hours daily and through intense exercise.

These approaches also can prompt the beiging of white fat. Most of us probably have some combination of fat cell types: mostly white, less beige and even less brown, she says.

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Prolonged periods of excess energy storage lead to weight gain and obesity. This excess energy is stored in white adipose tissue (WAT), which is the major fat storage depot and is linked to metabolic disease states. Contrarily, brown adipose tissues (BAT) dissipates energy as heat and consequently modulates daily energy expenditure (1). As the amount of metabolically active BAT is limited in patients with obesity and type two diabetes (T2D), alternatives are required to increase energetic expenditure via thermogenesis (2–6).

In addition to classic brown adipocytes, human adults have inducible brown adipocytes (named as brown-in-white or beige) with unique characteristics that differentiate them from both white and brown adipocytes (1, 7–10). Inducing beige adipocytes formation in WAT (browning) potentially decreases the negative effects of excess WAT and improves overall metabolic health (11). In response to cold exposure, inducible BAT greatly increases mitochondria and uncoupling protein 1 (UCP1) abundance. Additionally, after browning stimuli are removed, there is a rapid decrease of the thermogenic gene expression.

This dynamic response in beige fat can be contrasted with classic BAT where the levels of UCP1 and mitochondria are constitutively high (12, 13). Although numerous studies have identified several regulators of browning and thermogenesis, the molecular basis underlying beige adipocyte reversibility is yet to be understood (14–20).

Development and Origin of Brown and Beige Adipocytes

Beige adipocytes mainly reside in subcutaneous white adipose tissue (scWAT) depots (8). The scWAT depots in humans include cranial, facial, abdominal, femoral, and gluteal depots. In rodents, scWAT includes the anterior subcutaneous white adipose tissues (ascWAT) and the posterior subcutaneous adipose tissue (pscWAT) which itself includes inguinal, gluteal, and dorso-lumbal WAT (7, 21). BAT depots are distributed in the thoracic (mediastinal) and scapulae (interscapular, cervical, and axillary) areas of mice and rats (22). In humans, BAT was initially thought to exist only in the neck and shoulder of infants (23). However, later studies found active BAT in the paracervical and supraclavicular as well as in the anterior neck regions of adult humans (23–27).

In mammals, BAT is formed earlier during embryogenesis as compared to WAT. In human fetuses BAT formation begins early in the second trimester primarily in the head and neck regions and later in development forms in the trunk as well as in upper and lower limbs. The development of subcutaneous white adipose tissue is completed prenatally (28). In rodents, functional thermogenic BAT is formed 2 days before birth (E18–19) (29–32) and the development of scWAT continues postnatally (33–35).

Both white and brown adipose tissues are known to have mesodermal origins including the intermediate and lateral plate as well as the axial, and paraxial mesoderm. The paraxial mesoderm gives rise to BAT (36), and though the origin of scWAT is still debated, the progenitors of scWAT are known to originate from both the mesoderm and neuroectoderm (37–40). Furthermore, each fat depot includes numerous distinct progenitor fields that vary with age, gender, and environmental conditions. Additionally, scWAT depots are mainly derived from paired related homeobox 1 (PRX1) expressing progenitors (41–45).

Despite the previous view that myogenic factor 5 (MYF5), paired box 7 (PAX7), and paired box 3 (PAX3) expressing progenitors only give rise to BAT, it is now believed that the scWAT depots of the dorsal–anterior body region originated partly from those progenitors (9, 39, 46–49).

While ex vivo studies reported the presence of both PDGFRα and PDGFRβ in adipocyte stem cells (ASCc) (50), in adult mouse progenitors are heterogeneous and either express PDGFRα or PDGFRβ (51, 52). A recent study by Gao et al. suggested that the balance between PDGFRα and PDGFRβ determines whether progenitors will commit to beige (PDGFRα) or white (PDGFRβ) adipocytes (53). Some satellite cell-derived myoblasts in skeletal muscle and fibro-adipogenic progenitors (FAPs) also give rise to beige fat with higher rate of glycolysis and hence, named as glycolytic beige adipocyte (54).

Browning: Paths and Players

The increase of UCP1 positive, multilocular, thermogenic beige adipocytes within WAT (browning) is a potential therapeutic approach to increase insulin sensitivity and combat metabolic diseases such as obesity (102, 103). In mammals all browning features can be achieved by adrenergic stimulation, the main signaling pathway of thermogenic BAT which is induced by cold temperatures. In addition, several alternatives to this canonical pathway have been reported to regulate browning of WAT through interorgan crosstalk (104).

Several browning agents have been reported that are extensively reviewed elsewhere (20, 105–107) (Figure 1). For example, numerous pharmacological small molecules, dietary compounds, and nutritional agents are known to increase WAT browning (108–111). Additionally, various organs respond to environmental challenges such as cold, fasting, feeding, and exercise by secreting several factors and hormones that contribute to the browning (3, 112). Gut microbiota as well as immune cells and macrophages influence WAT browning process and have been well-discussed by others (113–115).

In mammals, increased energy expenditure and browning of WAT after gastric bypass surgery have been reported (116–118). The link between WAT browning and thermogenesis is supported by generic mouse models of UCP1 knockout and BAT paucity, both leading to compensatory browning of WAT (119, 120).

Beige adipocytes form via three main processes (121): (I) proliferation and de novo differentiation of beige adipocytes from the progenitor pool located in adipose vasculature mural cells and express smooth muscle actin (SMA), myosin-11 (MYH-11), and PDGFRα (122, 123). In addition to adipose tissue vasculature, smooth muscle cells are also proposed as a source of beige progenitors (124); (II) transdifferentiation of mature white adipocytes to beige adipocytes (12, 125) where adrenergic stimulation by cold and high-fat diet feeding increases de novo formation of beige adipocytes as well transdifferentiation of mature white cells into beige adipocytes (16, 51, 126, 127); (III) the activation of dormant beige adipocytes without the involvement of progenitors contributes to the formation of thermogenic beige fat (12, 128, 129). These competing hypotheses remain unresolved as current lineage tracing technologies are unable to distinguish between white-to-beige adipocyte transdifferentiation and the activation of dormant beige cells. The current strategies for lineage tracing are summarized by Sebo and Rodeheffer (129).

WAT Browning in Humans

Recent studies that carried out FDG-PET/CT imaging were able to identify BAT activity in supraclavicular, cervical, axillary, and less often in abdominal, mediastinal, and paraspinal fat depots. The UCP1 positive fat depots in adult humans detected as 18F-FDG positive contained both classical brown adipocytes as well as beige adipocytes (6, 11, 24, 26, 130–135). Beige and brown fat activity in humans is increased in response to cold exposure and is inversely associated with age, body mass index, and the levels of circulating lipid and glucose (24, 25, 136–141).

Studies have shown that even in lean people with larger BAT depot, the cold induced thermogenic function of BAT does not significantly impact energy balance (142, 143). Hence, targeting the large scWAT for browning to increase thermogenesis has recently become a target for therapeutic approaches. So far, the browning of WAT in humans has only been reported under extreme conditions and its contribution to energy expenditure compared to BAT is minor (144–146). Ten days of cold exposure in humans was insufficient to induce WAT browning, despite increasing BAT activity. This indicates a requirement for higher levels of adrenergic stimuli (147, 148).

The effects of prolonged physical training on human scWAT browning and increasing the levels of circulating adiponectin, apelin, irisin, and FGF21 are in line with improved metabolic health (145, 149). Additionally, severe weight loss in cancer patients as well as in obese patients going through weight loss surgeries leads to increased browning (150, 151). Prolonged elevations in norepinephrine levels as a consequence of burn injury also leads to increased scWAT browning and thermogenesis (152). Surgical trauma, not necessarily related to the incision, is also linked to local and distal WAT browning in humans (153).

Beige Reversibility and Maintenance

The thermogenic phenotype of beige adipocytes is reversible upon withdrawal of the external stimuli. Upon removal of adrenergic stimulation (for example in warm temperature), beige fat will gradually convert into cells with a unilocular lipid droplet and will progressively lose beige characteristics while increasing the white characteristics (e.g., reduced mitochondria and thermogenesis). This beige-to-white transformation is accompanied by reduced innervation, vasculature, and UCP1 expression and increased neural chemorepellent (semaphorin III) secretion and leptin expression (154–156).

Although beige phenotype reversibility seems like a recent hallmark of adipocyte plasticity, it has been reported for decades (157–160). The phenotypic and morphological conversion found in beige fat upon withdrawal of stimuli is not observed in classical brown adipocytes (46). In 2013, Christian Wolfrum’s research team used lineage tracing to validate beige-white interconversion.

They showed that the cold-induced beige fat was reversed within 5 weeks of warm temperature and almost 75% of the whitened beige adipocyte could become beige again upon cold induction. Interestingly, after a second cold exposure, half of the beige adipocytes were formed from the former whitened beige adipocytes and the other half of the newly formed beige adipocytes seemed to come from a different source (12).

Though the beige adipocytes lost their brown-like phenotype and acquired a white-like phenotype when the temperature was increased, they kept their epigenetic memory of the cold exposure which allowed them to activate browning genes as soon as they were exposed to cold temperatures (91). Interestingly, beige fat apoptosis and death was not found to be the cause of beige phenotype loss (12). Contrarily, BAT whitening was shown to increase cell death by increasing adipose inflammation, indicating a lack of plasticity in BAT (161). In 2015, Kozak and his research team reported much higher dynamics in UCP1 and mitochondrial turnover in beige fat when compared to BAT (162). In 2016, Kajimura and his research team elegantly linked the beige-to-white transition to mitochondrial disappearance (mitophagy).

Mitophagy increased upon adrenergic stimuli withdrawal and was shown to be mediated by parkin (PARK2) recruitment to the mitochondria. Inhibition of autophagy via deletion of autophagy-related 5 (ATG5), autophagy-related 12 (ATG12), and PARK2 maintained the beige phenotype after stimuli removal. By monitoring single-cells, the same study also observed direct transdifferentiation from beige-to-WAT which did not involve an intermediate step (163).

Recently, a natural and more stable beige adipose depot called thigh adipose tissue (tAT) was identified in mice (164). In contrast to classic beige adipocytes, tAT seems rather stable and maintains a beige fat phenotype in warm temperatures. However, high-fat diet (HFD) feeding and aging increased the white phenotypic features of tAT including the presence of unilocular adipocytes. Browning stimuli can increase brown adipocyte gene expression in tAT to a higher level than in iWAT. Furthermore, tAT has a higher rate of energy expenditure and lower expression of inflammatory genes relative to iWAT (164).

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499124/

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More information: De-Huang Guo et al, Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice, Nature Communications (2021). DOI: 10.1038/s41467-021-24540-8