The Endocrine Society

The concept that the gut microbiota serves as a virtual endocrine organ arises from a number of important observations. Evidence for a direct role arises from its metabolic capacity to produce and regulate multiple compounds that reach the circulation and act to influence the function of distal organs and systems. For example, metabolism of carbohydrates results in the production of short-chain fatty acids, such as butyrate and propionate, which provide an important source of nutrients as well as regulatory control of the host digestive system. This influence over host metabolism is also seen in the ability of the prebiotic inulin to influence production of relevant hormones such as glucagon-like peptide-1, peptide YY, ghrelin, and leptin. Moreover, the probiotic Lactobacillus rhamnosus PL60, which produces conjugated linoleic acid, has been shown to reduce body-weight gain and white adipose tissue without effects on food intake. Manipulating the microbial composition of the gastrointestinal tract modulates plasma concentrations of tryptophan, an essential amino acid and precursor to serotonin, a key neurotransmitter within both the enteric and central nervous systems. Indirectly and through as yet unknown mechanisms, the gut microbiota exerts control over the hypothalamic-pituitary-adrenal axis. This is clear from studies on animals raised in a germ-free environment, who show exaggerated responses to psychological stress, which normalizes after monocolonization by certain bacterial species including Bifidobacterium infantis. It is tempting to speculate that therapeutic targeting of the gut microbiota may be useful in treating stress-related disorders and metabolic diseases.

Dietary and xenobiotic compounds can disrupt endocrine signaling, particularly of steroid receptors and sexual differentiation. Evidence is also mounting that implicates environmental agents in the growing epidemic of obesity. Despite a long-standing interest in such compounds, their identity has remained elusive. Here we show that the persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces the differentiation of adipocytes in vitro and increases adipose mass in vivo. TBT is a dual, nanomolar affinity ligand for both the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor γ (PPARγ). TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased epididymal adipose mass in adults. In the amphibian Xenopus laevis, ectopic adipocytes form in and around gonadal tissues after organotin, RXR, or PPARγ ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPARγ activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.

Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-β (ERβ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERβ-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERβ-inactivated than in WT mice, demonstrating that ERβ reduces estrogen receptor-α (ERα)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERα-inactivated mice was intermediate between that seen in WT and ERαβ double-inactivated mice. Thus, ERβ inhibits ERα-mediated gene transcription in the presence of ERα, whereas, in the absence of ERα, it can partially replace ERα. In conclusion, our in vivo data indicate that an important physiological role of ERβ is to modulate ERα-mediated gene transcription supporting a “Ying Yang” relationship between ERα and ERβ in mice.