natural predators, including cats and rats. this occurs even in laboratory mice that have been isolated from predators for hundreds of generations. when the chemical cues responsible for the fear response were purified from cat saliva and rat urine, two homologous protein signals were identified: fel d 4 (felis domesticus allergen 4; q5vfh6), the product of the cat mup gene, and rat n 1 (rattus norvegicus allergen 1; p02761), the product of the rat mup13 gene. mice are fearful of these mups even when they are made in bacteria, but mutant animals that are unable to detect the mups showed no fear of rats, demonstrating their importance in initiating fearful behaviour. it is not known exactly how mups from different species initiate disparate behaviours, but mouse mups and predator mups have been shown to activate unique patterns of sensory neurons in the nose of recipient mice. this implies the mouse perceives them differently, via distinct neural circuits. the pheromone receptors responsible for mup detection are also unknown, though they are thought be members of the v2r receptor class. allergens the three-dimensional structure of equ c 1, shown in the crystallized dimeric form. the structure is resolved from 1ew3. along with other members of the lipocalin protein family, major urinary proteins can be potent allergens to humans. the reason for this is not known; however, molecular mimicry between mups and structurally similar human lipocalins has been proposed as a possible explanation. the protein product of the mouse mup6 and mup2 genes (previously mistaken as mup17 due to the similarity among mouse mups), known as mus m 1, ag1 or ma1, accounts for much of the allergenic properties of mouse urine. the protein is extremely stable in the environment; studies have found 95% of inner city homes and 82% of all types of homes in the united states have detectable levels in at least one room. similarly, rat n 1 is a known human allergen. a us study found its presence in 33% of inner city homes, and 21% of occupants were sensitized to the allergen. exposure and sensitization to rodent mup proteins is considered a risk factor for childhood asthma and is a leading cause of laboratory animal allergy (laa)—an occupational disease of laboratory animal technicians and scientists. one study found that two-thirds of laboratory workers who had developed asthmatic reactions to animals had antibodies to rat n 1. mup genes from other mammals also encode allergenic proteins, for example fel d 4 is primarily produced in the submandibular salivary gland and is deposited onto dander as the cat grooms itself. a study found that 63% of cat allergic people have antibodies against the protein. most had higher titres of antibodies against fel d 4 than against fel d 1, another prominent cat allergen. likewise, equ c 1 (equus caballus allergen 1; q95182) is the protein product of a horse mup gene that is found in the liver, sublingual and submaxillary salivary glands. it is responsible for about 80% of the antibody response in patients who are chronically exposed to horse allergens. metabolism while the detection of mups excreted by other animals has been well studied, the functional role in the producing animal is less clear. however, in 2009, mups were shown to be associated with the regulation of energy expenditure in mice. scientists found that genetically induced obese, diabetic mice produce thirty times less mup rna than their lean siblings. when they delivered mup protein directly into the bloodstream of these mice, they observed an increase in energy expenditure, physical activity and body temperature and a corresponding decrease in glucose intolerance and insulin resistance. they propose that mups' beneficial effects on energy metabolism occurs by enhancing mitochondrial function in skeletal muscle. another study found mups were reduced in diet-induced obese mice. in this case, the presence of mups in the bloodstream of mice restricted glucose production by directly inhibiting the expression of genes in the liver.