Discovery of ACBP Molecule Sheds Light on Fat-Burning Tissue Suppression and Metabolic Disease

Obesity, diabetes, and cardiovascular disease are increasingly common in the population. Brown adipose tissue plays a protective role against these prevalent diseases, as it burns calories and can generate body heat from fat. However, as the body ages, brown adipose tissue activity decreases. This inactivation of brown adipose tissue, also typical in obese individuals, remains understudied in the scientific literature. A study shows that ACBP molecule plays a key role in the regulation of brown adipose tissue (BAT).

Now, a study published in Molecular Metabolism has identified, for the first time, a molecule capable of suppressing the activity of brown adipose tissue. This discovery opens new avenues for understanding the mechanisms that lead to the inactivation of this type of tissue, which is fundamental to fat metabolism.

Furthermore, it raises the possibility of reversing this repressive function, which could contribute to the development of new therapeutic strategies against obesity and cardiometabolic diseases.

The ACBP molecule

The study demonstrates that the ACBP molecule plays a key role in the regulation of brown adipose tissue (BAT) by acting as a potent inhibitor of its thermogenic activity. The researchers observed that, in response to stimuli related to cold or noradrenergic activation, the expression and release of ACBP by brown adipocytes decreases significantly, which facilitates BAT activation. This reduction appears to be linked to intracellular mechanisms such as autophagy and inhibition of Acbp gene transcription .

In mouse models, targeted deletion of the ACBP gene in BAT resulted in transcriptome remodeling and histological changes consistent with increased heat-generating capacity. These animals also showed improved overall metabolic status, both under normal and obesogenic conditions, with improvements in glucose regulation and protection against the development of obesity, without implying altered caloric intake. The observed increase in energy expenditure suggests that the absence of ACBP enhances the thermogenic function of BAT.

The observed effects were not limited to the interscapular brown fat (iBAT) depot, as changes were also recorded in similar tissues such as perivascular adipocytes. This reinforces the idea that the local action of ACBP—whether intracellular, autocrine, or mediated by vascular secretion—can have systemic repercussions.

Upregulation of cold-stimulated genes

Transcriptomic analysis of BAT in these models identified upregulation of several genes commonly stimulated by cold and noradrenergic signals, including Gsta3 and Dhrs9, which have not previously been associated with brown adipose tissue biology. Their functional implications will require further investigation.

Furthermore, circulating ACBP levels were unaffected by BAT-specific deletion , suggesting that this tissue contributes little to systemic ACBP or that other organs may compensate for its production. Nevertheless, the local impact on BAT activity was evident, pointing to a key role for ACBP in the intrinsic regulation of energy metabolism.

In vitro experiments confirmed that extracellular ACBP can significantly suppress the metabolic and thermogenic activity of brown adipocytes, in addition to inducing proinflammatory signaling. This action includes the inhibition of essential intracellular pathways, such as p38 MAP kinase activation and CREB phosphorylation, processes critical for initiating the thermogenic response.

Role of the GABA-A receptor

Although the cellular receptor responsible for these effects has not yet been precisely determined, previous studies point to the GABA-A receptor as a mediator of ACBP action in the brain , and a possible involvement of its gamma-2 subunit in peripheral tissues has been identified.

According to transcriptomic databases, the expression levels of these subunits are elevated in BAT and tend to decrease when the tissue is activated by cold , reinforcing the hypothesis of a regulatory role of the ACBP/GABA-A axis in thermogenesis.

Furthermore, blocking ACBP in culture media using antibodies partially replicated the effects observed with its genetic inhibition, including the promotion of lipolysis, suggesting a possible therapeutic approach.

Taken together, the findings reveal the existence of an autoregulatory mechanism in which BAT activation reduces ACBP expression , while this molecule, in turn, represses tissue thermogenic activity, generating a negative feedback loop. Under high temperature conditions, ACBP expression and secretion increase, which could contribute to inhibiting BAT activity.

Elevated levels of ACBP have been linked to obesity, diabetes, inflammation, cardiometabolic diseases, and aging, all of which are associated with low BAT activity. These results support the hypothesis that ACBP blockade—both locally and systemically— could have therapeutic benefits in various metabolic pathologies.

It is also suggested that ACBP modulation could be useful for controlling clinical situations in which excessive BAT activity is detrimental, such as in cases of cancer-related cachexia or hypermetabolism following severe burns.

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First published in GACETA MEDICA. A third-party contributor translated and adapted the article from the original. In case of discrepancy, the original will prevail.

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