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The pancreas is a mixed gland primarily composed of exocrine tissue, which secretes digestive enzymes into the digestive tract, and an endocrine component organized into small clusters known as islets of Langerhans, constituting approximately 1% of the pancreatic mass. Each adult islet contains an average of 1,500 cells, including beta-, alpha- and delta-cells, which produce and secrete insulin (INS), glucagon (GCG), and somatostatin (SST) respectively. The destruction of insulin-producing beta-cells or the defective insulin secretion give rise to type 1 and type 2 diabetes mellitus, respectively. These chronic metabolic disorders are characterized by the dysregulation of glucose homeostasis. 

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Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging

Yoon Namkung, Tal Slutzki, Joao Pedroso, Xiaohong Liu, ... Stéphane A. Laporte

Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging

 

Objective

The central melanocortin system, composed of peptides derived from pro-opiomelanocortin (POMC) such as the melanocyte-stimulating hormones (α-, β-, γ-MSH) and melanocortin 4 receptors (MC4R), along with the agouti-related protein (AgRP), plays a pivotal role in controlling energy balance. To elucidate the dynamic role of α-MSH release in regulating appetite, specific, sensitive, and spatiotemporally resolved genetic sensors are required.

Methods

The melanocortin 1 receptor (MC1R) scaffold was leveraged for its robust plasma membrane expression, high affinity for melanocortins and low affinity for AgRP to design a α-MSH selective sensor for in vivo use. This was achieved by integrating circularly permuted green fluorescent protein (cpGFP) into the receptor, which we named Fluorescence Amplified Receptor sensor for Melanocortin (FLAREMC).

Results

The FLAREMC sensor has high potency and selectivity in heterologous and homologous expressing cells for α-MSH and the synthetic melanocortin agonist MTII but not to the inverse agonist AgRP. The sensor exhibited impaired signaling, with reduced G protein activation, no β-arrestin coupling, and failed to internalize upon agonist stimulation. In vitro, FLAREMC displayed high photostability and reversible photoactivation. These properties suggest that the FLAREMC is suitable for long-term activity recording in the brain without desensitizing or interfering with endogenous melanocortin receptor signaling. When expressed in the paraventricular nucleus (PVN) of the mouse hypothalamus, the primary site of anorexigenic α-MSH signaling, FLAREMC demonstrated its effectiveness in detecting changes associated with melanocortin responses in vivo.

Conclusions

FLAREMC enables the study of melanocortin system in cultured cells and in vivo. This first of its class highly sensitive melanocortin sensor will serve as a valuable tool to advance our understanding of the complex dynamics governing melanocortin-dependent appetite regulation and related processes in the brain.

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Articles in Press

Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging

Yoon Namkung, Tal Slutzki, Joao Pedroso, Xiaohong Liu, ... Stéphane A. Laporte

Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging

 

Objective

The central melanocortin system, composed of peptides derived from pro-opiomelanocortin (POMC) such as the melanocyte-stimulating hormones (α-, β-, γ-MSH) and melanocortin 4 receptors (MC4R), along with the agouti-related protein (AgRP), plays a pivotal role in controlling energy balance. To elucidate the dynamic role of α-MSH release in regulating appetite, specific, sensitive, and spatiotemporally resolved genetic sensors are required.

Methods

The melanocortin 1 receptor (MC1R) scaffold was leveraged for its robust plasma membrane expression, high affinity for melanocortins and low affinity for AgRP to design a α-MSH selective sensor for in vivo use. This was achieved by integrating circularly permuted green fluorescent protein (cpGFP) into the receptor, which we named Fluorescence Amplified Receptor sensor for Melanocortin (FLAREMC).

Results

The FLAREMC sensor has high potency and selectivity in heterologous and homologous expressing cells for α-MSH and the synthetic melanocortin agonist MTII but not to the inverse agonist AgRP. The sensor exhibited impaired signaling, with reduced G protein activation, no β-arrestin coupling, and failed to internalize upon agonist stimulation. In vitro, FLAREMC displayed high photostability and reversible photoactivation. These properties suggest that the FLAREMC is suitable for long-term activity recording in the brain without desensitizing or interfering with endogenous melanocortin receptor signaling. When expressed in the paraventricular nucleus (PVN) of the mouse hypothalamus, the primary site of anorexigenic α-MSH signaling, FLAREMC demonstrated its effectiveness in detecting changes associated with melanocortin responses in vivo.

Conclusions

FLAREMC enables the study of melanocortin system in cultured cells and in vivo. This first of its class highly sensitive melanocortin sensor will serve as a valuable tool to advance our understanding of the complex dynamics governing melanocortin-dependent appetite regulation and related processes in the brain.

  •  

 

 

2022 impact factor: 6.6

You are what you eat

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