Math
Explanation
The Joke
Someone complains to God: "Why is the universe made of such gutty math?" (difficult, unpleasant mathematics). God asks "What?" and the person explains: planning a route requires freaking difficult algorithms, discovering the origin of the universe requires spending one's whole life suffering through equations, and finding the best route between friends requires similarly grueling computation. They conclude: "The physicists use my math!"
God (or a female figure representing a muse/nature) responds: "That's because they never leave the office." The joke implies that the math is only "gutty" because the people doing it are disconnected from the physical world it describes.
The Humor
The comic plays on the common complaint that the mathematics underlying reality is unreasonably difficult. Why should planning a simple road trip require solving computationally hard optimization problems (like the Traveling Salesman Problem)? Why should understanding the cosmos require decades of advanced mathematics?
The punchline subverts the complaint by suggesting the problem isn't the math — it's the mathematicians. The response "they never leave the office" implies that if physicists and mathematicians actually went outside and experienced the world directly, maybe the math wouldn't seem so bad. This is a humorous inversion of Eugene Wigner's famous essay "The Unreasonable Effectiveness of Mathematics in the Natural Sciences" — instead of marveling at how well math describes reality, the comic complains about how unnecessarily hard the math is, then blames the people doing it for being shut-ins.