An international research team headed by scientists at the Institute of Diabetes and Obesity (IDO), Helmholtz Zentrum München, has discovered how a transcription factor called T-box 3 (Tbox3) acts as a molecular switch that regulates the functions of neurons in the brain that control satiety and appetite, and so body weight. The researchers’ studies in mice, fruit flies, and cultured human cells showed that lack of Tbox3 effectively disrupts the balance between these two sets of neurons, and could feasibly help to identify new therapeutic targets.

“Both in a preclinical model and in fruit flies, the absence of Tbx3 leads to a kind of identity crisis of satiety neurons, resulting in obesity,” commented Alexandre Fisette, PhD, co-lead author of the researchers’ published paper in Nature Metabolism and a senior postdoctoral fellow at Helmholtz Zentrum München. The researchers’ in vitro tests also indicated that a similar control pathway may be at work in humans. “In preliminary experiments with human neurons, we were able to show that they are no longer able to carry out their function in the absence of Tbx3,” added co-lead author Carmelo Quarta, PhD, a postdoc at Helmholtz Zentrum München.

The IDO researchers and colleagues described their findings in a paper titled, “Functional identity of hypothalamic melanocortin neurons depends on Tbx3.”

The body’s natural ability to maintain energy balance is regulated by different kinds of energy-sensing neurons in the brain that work together to control appetite and energy expenditure. “Whether we’re hungry or feel full is largely determined by the brain—specifically in the hypothalamus,” explained Fisette. “Two groups of neurons in the hypothalamus control body weight and energy balance via various molecular messengers. Like yin and yang, they help strike a good balance.” These two brain cell populations are propiomelanocortin (Pomc)-expressing neurons, which produce sensations of satiety, and agouti-related protein (Agrp)-expressing neurons, which increase appetite. However, if the interplay between the two neuronal populations is disturbed, obesity or type 2 diabetes can result.

The latest work by the IDO-led team has now found that the transcription factor Tbx3 is critical to the differentiation and function of these neurons in the hypothalamic arcuate nucleus (ARC). Tbx3 had previously been shown to influence the proliferation, fate commitment, and differentiation of different non-neuronal cell types but, as the researchers pointed out, “its functional role during neuronal development or in post-mitotic neurons located in the CNS [central nervous system] is unchartered.” Interestingly, prior work had also linked mutations in the Tbx gene in humans with a syndrome that causes impaired puberty, growth hormone deficiency, and obesity.

The new IDO-led research in mice demonstrated that loss of Tbx3 in Pomc-expressing hypothalamic neurons caused weight gain, glucose intolerance, and increased fat mass, when compared with control animals. “… in the absence of Tbx3, the neurons responsible for producing a feeling of satiety are no longer able to synthesize the expected molecular messengers,” Quarta stated. “These metabolic alterations are accompanied by a massive decrease in the number of Pomc-expressing neurons during postnatal life, independently of changes in cell number, which probably underlies the observed obesity phenotype,” the authors further commented. Using further experimental techniques the team subsequently confirmed that Tbx3 played a pivotal role in maintaining energy and sugar metabolism, was critical for the differentiation of Pomc neurons during development, and also controlled the identity and plasticity of mature Pomc neurons. “Tbx3 affects systemic energy homeostasis by controlling the peptidergic identity profile of different populations that directly modulate the activity of the melanocortin system in ARC neurons during neonatal life, when maturation of the melanocortin system occur,” the researchers noted.

In the fruit fly Drosophila melanogaster knockdown of the Tbx3 homologue, Omb, resulted in increased fat accumulation when compared with control flies, while deleting the Tbx3 gene in an in vitro human cell system disrupted neuronal differentiation. “Together, these data reveal that TBX3 is essential for the maturation of hypothalamic progenitors into ARC-like POMC-expressing neurons,” the authors wrote. While they suggest that the findings highlight a conserved role for Tbx3 in the regulation of energy homeostasis in invertebrates and in mammals, including humans, they also acknowledge that the molecular and cellular mechanisms that underpin these effects might differ across different species. Drosophila, for example, doesn’t express Pomc Agrp or any homologue peptide. “Our observations in Drosophila melanogaster suggest that the link between neuronal Tbx3 action and systemic energy homeostasis is probably evolutionarily conserved … ” they stated. “… however, our data do not enable understanding of the cellular and molecular mechanisms underlying the obese-like phenotype observed in flies or whether these mechanisms are conserved across different species.”

Nevertheless, they concluded, “we uncovered a molecular switch implicated in the terminal differentiation of body-weight-regulating ARC neurons into specific peptidergic subtypes, unraveling one of the mechanisms responsible for the neuronal heterogeneity of hypothalamic ARC neurons. Our findings represent another step toward the identification the key molecular machinery controlling the functional identity of hypothalamic neurons, particularly during postnatal life, and may consequently facilitate understanding of the fundamental neuronal mechanisms implicated in the pathogenesis of obesity and its associated metabolic perturbations.”

“Our study explains for the first time the underlying mechanisms and once again focuses attention on the central role of the brain in regulating energy metabolism,” stated study director Matthias H. Tschöp, PhD, CEO of Helmholtz Zentrum München and holder of the chair for metabolic diseases at the Technical University of Munich. “We hope that Tbx3 may come into consideration one day as a target for drug therapies.”

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