Microbiota depletion promotes browning of white adipose tissue and reduces obesity

Abstract

Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity1. In response to cold or exercise brown fat cells also emerge in the white adipose tissue (named beige cells), a process known as browning2,3,4. Here, we show that the development of functional beige fat is promoted by microbiota depletion either by antibiotic treatment or in germ-free mice within the inguinal subcutaneous and perigonadal visceral adipose tissues (ingSAT and pgVAT, respectively). This leads to improved glucose tolerance, insulin sensitivity and decreased white fat and adipocyte size in lean mice and obese leptin-deficient (ob/ob) and high fat diet (HFD)-fed mice. These metabolic improvements are mediated by eosinophil infiltration and enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by suppression of the type 2 signaling and are reversed by recolonization of the antibiotic-treated, or the germ-free mice with microbes. These results provide insight into microbiota-fat signaling axis and beige fat development in health and metabolic disease.

Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling

“…We note that a common feature between the cold exposure and endurance exercise is the negative energy balance: higher energy expenditure than intake leading to fat loss. In addition, interventional microbiota depletion, either by means of antibiotics administration or in germ-free mice (Suá rez-Zamorano et al, 2015;Chevalier et al, 2015), as well as RYGB (Neinast et al, 2015) also increase the browning to a similar extent as several endurance exercise regimens. These are also conditions of decreased caloric uptake and negative energy balance.…”

“…Browning appears consequent to physiological stimuli, such as cold exposure or endurance exercise (Cousin et al, 1992;Guerra et al, 1998;Himms-Hagen et al, 2000). In addition to the physiological stimuli, also microbiota depletion (Suá rez-Zamorano et al, 2015;Chevalier et al, 2015) and Roux-en-Y gastric bypass weight-loss surgery (RYGB) (Neinast et al, 2015) promote the development of beige fat. It remains unclear whether there is a common feature between these seemingly unrelated physiological and interventional stimuli that could lead to the beige fat development.…”

Mechanisms of metabolic dysfunction in cancer-associated cachexia

“…Indeed, macrophages infiltrate the WAT of cachectic mice and express markers of alternative activation. The link between the immune system and adipose tissue biology is further supported by recent investigations showing WAT browning following microbiota depletion (Suarez-Zamorano et al 2015;Yeoh and Vijay-Kumar 2015). Interestingly, colonization of the intestine by different strains of bacteria has been shown to modulate disease severity and cachexia development in mouse models (Schieber et al 2015).…”

Exercise and Dietary Factors Affecting the Microbiota: Current Knowledge and Future Perspectives

“…Browning of the white adipose tissue was associated with improved glucose tolerance, and insulin sensitivity in lean, ob/ob and HFD mice. The browning process was present as soon as 10 days after microbiota antibiotic-induced depletion and further increased after 40-60 days [33]. Whether this effect is conserved in the human species remains to be discovered.…”

“…Nonetheless, beneficial effects of the gut microbiota have been demonstrated on necrotizing enterocolitis, acute diarrheal infections, ulcerative colitis, and irritable bowel syndrome [33]. A shift from obligate anaerobes (Faecalibacterium prausnitzii) to facultative anaerobes (Enterobacteriaceae) takes place in the elderly and in inflammatory bowel diseases, thus, favoring pathogenic bacteria and inflammation [8,35].…”