Disturbed FURIN enzyme in brain can make you gain weight

(FURIN enzyme is one of the key regulators of energy balance. When the FURIN enzyme is disrupted can result in weight gain)

Author: Manish Verma

Editor: Dr. Jitendra Kumar Sinha

Hypothalamus is almost an almond-size brain region located under (that’s why hypo-) the thalamus and above the pituitary gland. This brain region is known to play multiple crucial roles in controlling mood, thirst, temperature, heart rate, eating patterns, energy expenditure, and sleep. Interestingly, the key to controlling these complex behavioral and physiological outputs lies in the neural circuitry and chemical interactions in the hypothalamus. In this context, a key molecular circuit in the melanocortin system employs a push-and-pull way to control food intake.

Neuropeptide hormones, also known as melanocortins, such as adrenocorticotropic hormone (ACTH) and α-melanocyte-stimulating hormone (MSH), are produced solely in the hypothalamic arcuate nucleus.

There are two sets of neurons in this circuit that works in an antagonistic fashion: the agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons, which stimulate feeding behavior, and the pro-opiomelanocortin (POMC) neurons, promoting satiety post-meal.

The synthesis of these hormones and their receptors requires POMC (proopiomelanocortin) to undergo proteolytic cleavage by proprotein convertases (PCs) such as PC1/3 and PC2. (See Fig.1) In PC1/3-deficient individuals, POMC is cleaved into ACTH and β-lipotropin, which would otherwise result in obesity, hyperphagia, and endocrinopathies. PC2 further cleaves ACTH into α-MSH, which increases the risk of type 2 diabetes in PC2 null patients.

Figure 1 – Cleavage of POMC by FURIN proceeds selectively at the C-terminal location of ACTH. (Reproduced directly from Ilaria et al., 2022)

In a recently published study by Ilaria et al., the researchers tried to investigate the role of FURIN in the processing and maturation of POMC, and how it modulates glucose and feeding mechanisms in hypothalamic neurons of POMCFur knockout mice.

FURIN is a proteolytic enzyme produced by the FURIN gene that cleaves the inhibitors of PC1/3 and PC2, thereby contributing to energy and glucose balance. Also, FURIN activity in beta cells is required for insulin receptor (IR) activation and, by extension, the control of insulin signaling. Several cancer cell lines and certain animal tissues also utilize the IR as a FURIN substrate. Importantly, IR plays a critical role in the brain in regulating glucose homeostasis throughout the body.                                                                          

In their experiment, the researchers fed normal (NCD) and high-fat (HFD) diets to both control and POMCfurKO mice in order to study body weight and glucose tolerance. Upon biochemical investigations, the results indicated that POMC processing was significantly reduced in the hypothalamus of POMCFurKO mice, highlighting the involvement of FURIN in the cleavage of POMC. FURIN deficiency in POMC neurons resulted in an increase in body weight and food intake. This demonstrates a connection between metabolic conditions and the FURIN-dependent processing of neuropeptides.

When HFD was fed to control mice, FURIN mRNA levels were significantly increased, suggesting that FURIN activity is aggravated in obesogenic conditions. Also, in cell lines without a regulated secretory pathway, FURIN got to the first stage of processing, where POMC is cut into proACTH but not PC1/3 or the other proprotein convertases.

To sum up, the FURIN enzyme is a key regulator of energy balance under obesogenic conditions, and its disruption can cause weight gain upon consuming a high-fat diet. However, further study is needed to determine the precise mechanisms and pathways involved.

Abbrevations:

POMC – pro-opiomelanocortin

PC – proprotein converteases

NPY – Neuropeptide Y

HFD – High Fat Diet

NCD – Normocaloric Diet

KO – Knockout

References:

  1. Coppola, I., Brouwers, B., Walker, L., Alar, C., Meulemans, S., White, A., Ramos-Molina, B., & Creemers, J. W. M. (2022). Loss of hypothalamic Furin affects POMC to proACTH cleavage and feeding behavior in high-fat diet-fed mice. Molecular metabolism, 66, 101627. Advance online publication. https://doi.org/10.1016/j.molmet.2022.101627
  2. Ghosh, S., Sinha, J. K., & Raghunath, M. (2019). ‘Obesageing’: Linking obesity & ageing. The Indian journal of medical research, 149(5), 610–615. https://doi.org/10.4103/ijmr.IJMR_2120_18
  3. Sachdeva, P., Ghosh, S., Ghosh, S., Han, S., Banerjee, J., Bhaskar, R., & Sinha, J. K. (2022). Childhood Obesity: A Potential Key Factor in the Development of Glioblastoma Multiforme. Life (Basel, Switzerland), 12(10), 1673. https://doi.org/10.3390/life12101673
  4. Jarvela, T. S., Shakya, M., Bachor, T., White, A., Low, M. J., & Lindberg, I. (2019). Reduced Stability and pH-Dependent Activity of a Common Obesity-Linked PCSK1 Polymorphism, N221D. Endocrinology, 160(11), 2630–2645. https://doi.org/10.1210/en.2019-00418

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