Dataset Information

Desacetyl-?-melanocyte stimulating hormone and ?-melanocyte stimulating hormone are required to regulate energy balance.

ABSTRACT:

Objective

Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (?-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-?-MSH, the precursor for ?-MSH, is present in brain and blood. Desacetyl-?-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with ?-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-?-MSH is still unclear.

Methods

We created a novel mouse model to determine whether desacetyl-?-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-?-MSH and ?-MSH from adrenocorticotropin (ACTH_1-39).

Results

The mutant ACTH_1-39 (ACTH^QKQR) functions similar to native ACTH_1-39 (ACTH^KKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH_1-39 (Pomc^tm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-?-MSH or ?-MSH over 14 days into Pomc^tm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomc^wt/wt) mice. Here, we identify both desacetyl-?-MSH and ?-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-?-MSH.

Conclusions

Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-?-MSH and ?-MSH.

SUBMITTER: Mountjoy KG

PROVIDER: S-EPMC5869732 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.

Mountjoy Kathleen G KG Caron Alexandre A Hubbard Kristina K Shome Avik A Grey Angus C AC Sun Bo B Bould Sarah S Middleditch Martin M Pontré Beau B McGregor Ailsa A Harris Paul W R PWR Kowalczyk Renata R Brimble Margaret A MA Botha Rikus R Tan Karen M L KML Piper Sarah J SJ Buchanan Christina C Lee Syann S Coll Anthony P AP Elmquist Joel K JK

Molecular metabolism 20171124

<h4>Objective</h4>Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC ...[more]

PMID: 29226825

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Project description:ObjectiveDuring infection, metabolism and immunity react dynamically to promote survival through mechanisms that remain unclear. Pro-opiomelanocortin (POMC) cleavage products are produced and released in the brain and in the pituitary gland. One POMC cleavage product, alpha-melanocyte-stimulating hormone (α-MSH), is known to regulate food intake and energy expenditure and has anti-inflammatory effects. However, it is not known whether α-MSH is required to regulate physiological anti-inflammatory responses. We recently developed a novel mouse model with a targeted mutation in Pomc (Pomctm1/tm1 mice) to block production of all α-MSH forms which are required to regulate metabolism. To test whether endogenous α-MSH is required to regulate immune responses, we compared acute bacterial lipopolysaccharide (LPS)-induced inflammation between Pomctm1/tm1 and wild-type Pomcwt/wt mice.MethodsWe challenged 10- to 14-week-old male Pomctm1/tm1 and Pomcwt/wt mice with single i.p. injections of either saline or low-dose LPS (100 μg/kg) and monitored immune and metabolic responses. We used telemetry to measure core body temperature (Tb), ELISA to measure circulating cytokines, corticosterone and α-MSH, and metabolic chambers to measure body weight, food intake, activity, and respiration. We also developed a mass spectrometry method to measure three forms of α-MSH produced in the mouse hypothalamus and pituitary gland.ResultsLPS induced an exaggerated immune response in Pomctm1/tm1 compared to Pomcwt/wt mice. Both groups of mice were hypoactive and hypothermic following LPS administration, but Pomctm1/tm1 mice were significantly more hypothermic compared to control mice injected with LPS. Pomctm1/tm1 mice also had reduced oxygen consumption and impaired metabolic responses to LPS compared to controls. Pomctm1/tm1 mice had increased levels of key proinflammatory cytokines at 2 h and 4 h post LPS injection compared to Pomcwt/wt mice. Lastly, Pomcwt/wt mice injected with LPS compared to saline had increased total α-MSH in circulation 2 h post injection.ConclusionsOur data indicate endogenous α-MSH contributes to the inflammatory immune responses triggered by low-dose LPS administration and suggest that targeting the melanocortin system could be a potential therapeutic for the treatment of sepsis or inflammatory disease.