Britain cannot "stand tall" in the world unless it remains part of the European Union, ex-Liberal Democrat leader Nick Clegg has said.
The former deputy prime minister also warned that a vote in favour of Brexit would trigger a fresh referendum on Scottish independence, leading to a break-up of the United Kingdom.
Mr Clegg said that as a consequence England would end up "drifting somewhere, friendless, in the mid-Atlantic, less relevant to world affairs".
The Lib Dem MP, who quit as leader after the party lost all but eight of its seats in the general election in May, made an impassioned plea for Britain to vote to remain in the EU when the referendum is held before the end of 2017.
"The world has changed fundamentally and it is unrecognisable from the days when Britain was able to shape its own destiny on its own terms without having to rely on the co-operation from other countries," Mr Clegg said.
"We can't stand tall in the world unless we stand tall in Brussels, Berlin and Paris. The simple idea that you get more done for us by working with others, I think, is a very important principle.
"The very fabric of our economy has become inextricably tied up with the European economy. Why on earth would we jeopardise that just as the country is recovering from the economic crash we experienced in 2008?
"If we do come out of the European Union it will have a bigger transformative effect on who we are, Britain, than many people might appreciate.
"Not only will we be cut off from one union, we will almost certainly lose our own union, as Scotland then leaves the UK.
"For England, we end up drifting somewhere, friendless, in the mid-Atlantic, less relevant to world affairs and less open to the world as well.
"However flawed the European Union, I just don't think a nation such as ours can exercise leadership in our own European hemisphere unless we remain part of the club of that hemisphere.
"Our tectonic plate is here and it is not going to move to another continent or hemisphere. We are condemned by geography and geology to be a European nation and we constantly wish it away."
Mr Clegg also warned of the dangers of rejecting the EU at a time of a rise in nationalism and identity politics across the world.
"We are witnessing a huge change in politics where people who have mobilised the public's understandable grievance about how they feel about the world is on the rise," he said.
"I think it would be a catastrophic mistake of huge proportions if we were to play into that rise in populism, us and them politics, by turning our backs on our own European hemisphere."
Mr Clegg was speaking during a debate at the Cheltenham Literature Festival on whether Britain should remain in the EU.
Also on the panel were Conservative MEP Daniel Hannan, former Labour foreign secretary and co-founder of the SDP Lord Owen, Innocent Drinks founder Richard Reed and Minette Batters, deputy president of the National Farmers' Union.
Mr Hannan told the audience: "We have to make our way in the world by what we buy and sell. Our trade with the EU is diminishing by the minute.
"Twenty years from now it is going to seem bizarre that we were having this argument about whether to merge our political system with the rest of the EU in order to have a say over what might be by then a quarter or a fifth of our total exports.
"I don't think the European Union is a terrible monstrosity, I just think we will be a little bit happier and a little bit wealthier if we leave and rejoin the rest of the world."
Lord Owen said there needed to be a "fundamental restructure" of the EU with the emphasis upon a single market rather than the eurozone.
"That opens up a 'new Europe' and if we were to do that I could see a Europe with a future. I'm a lifelong European and I have supported it and voted for it at every stage," he said.
"But at the moment this status is not capable of going on as it is and if we are not faced with a serious restructuring of Europe then we will have very little option in my view than to vote to leave."