An international collaborative study between Japanese and American scientists has revealed how a single hormone multi-tasks without muddling up its functions. The hormone in question is thyrotropin, the thyroid-stimulating hormone (TSH) that manages to activate seasonal sensing and regulate metabolism without any confusion.

TSH is secreted from the pituitary glands from two parts. TSH secreted from the front of the pituitary gland, pars distalis, goes on to stimulate the thyroid gland to secrete the hormone thyroxine, which plays a primary role in the regulation of metabolism.

TSH is also secreted from the stalk of the pituitary gland, pars tuberalis, and is known to act on the hypothalamus. While both proteins have the same structure, the exact role of TSH being secreted from the pars tuberalis was unknown until the Japanese team, led by Professor Takashi Yoshimura, discovered it acts as a novel spring-calling hormone, sending information and controlling how the body reacts to seasonal changes.

How Does TSH Act As A Spring-Calling Hormone?

Many activities of animals change with the onset of spring or change in the duration of night and day, such as seasonal breeding, bird migration, wool shedding, and hibernation. How the internal clocks of these animals were so attuned to the changing season was quite a mystery to researchers. Then, in 2008, the Japanese team identified the spring-calling hormone or the TSH secreted from the pars tuberalis (PT-TSH) in the pituitary gland that on arrival of spring or longer days sends information on seasonal changes to the hypothalamus in the brain.

Once this was discovered, the next question that baffled researchers was how the hormone performed these diverse biological functions of acting as a spring-calling hormone and a growth regulator without the two processes interfering in the blood stream.  

Their research, published the journal Cell Reports, found that the hormone accomplished this feat through tissue-specific glycosylation (attachment of sugars) and subsequent recognition by the immune system.

"It has been a great mystery on how the activities of TSHs were being differentiated. Initially, it has been suggested that TSHs arising from the pars tuberalis and pars distalis were being regulated differently at each source," Yoshimura said in a statement. "From our investigations on knock-out mice, we found that PD-TSH was being regulated by the thyrotropin-releasing hormone (TRH) secreted by the hypothalamus, whereas PT-TSH was not controlled by TRH but was being controlled by a hormone called melatonin, which is a hormone secreted by the pineal gland during the night."

While studying the structures of the PT-TSH and PD-TSH by MALDI mass spectrometry analysis, the team found that though they had similar protein structures, they had different carbohydrate chains attached to them. The carbohydrate chains in the PD-TSH could be easily metabolized while those in PD-TSH could form stable complexes with immunoglobulin and albumin present in the blood.

This tissue-specific glycosylation prevents each TSH from cross activity. Interestingly, this is the first time the role of tissue-specific glycosylation in preventing functional crosstalk between signaling molecules has been shown. 

This study may pave the way for further understanding elements in the field of glycobiology and immunology and provide insights into diseases caused by the abnormal synthesis and functioning of TSH, say the researchers.

Source: Ikegami k, Liao X, Hoshino Y. Tissue-specific post-translational modification allows functional targeting of Thyrotropin. Cell Reports. 2014.