Greetings everyone.

Sorry about the delay on this edition of The Arrow. I have a ton going on, so I took a week off for the first time in over four years. I wouldn’t have thought much about it if a zillion people hadn’t emailed me that they somehow didn’t get their copy of The Arrow last week. I should have sent out a brief note. Anyway, here I am back in action.

MD, Bob, and Me

Before I get started on the main section I’ve been working on for this edition, I would like to start with a personal anecdote. One of my favorite Substack writers is the highly educated Ted Gioia, who writes on a multitude of issues.

One of his recurring themes is taking a deep dive into a particular book and/or writer. Today’s post was all about Robert Pirsig and his famous book Zen and the Art of Motorcycle Maintenance, one of my favorite books.

I enjoyed the book so much that I actually slowed down my reading as I got toward the end because I didn’t want it to be over.

If you haven’t discovered by reading it yourself, Zen and the Art of Motorcycle Maintenance is a different kind of book that can’t really be categorized. Gioia delved deeply into the life of Pirsig and why he wrote the book. As much as I enjoyed Zen, I didn’t know much of anything about its author, because, at the time I read the book, there was no Google. In fact, there was no internet, and home computers were the things of science fiction. So it was difficult to do much research on any particular author, especially a new one.

I learned more from Gioia’s Substack than I knew before. But I did know the name of the publisher who bought the book, because Pirsig thanked him in the acknowledgments. He wrote that he had sent Zen to a hundred-and-twenty plus publishers without anyone taking a chance on it. Here’s a little excerpt from Gioia’s piece about that.

Here is where the personal anecdote comes in.

J.D. Landis was the publisher who bought what became Protein Power.

Our agent presented the book proposal for Protein Power (which wasn’t called Protein Power at that time; our working title was The Insulin Connection) to a number of publishers who were semi interested, but William Morrow and Company was the one who ended up buying it.

After the purchase, MD and I flew to New York to meet with our editor. When we got there, we met our editor face to face for the first time and discussed the book. She then told us we were all going to lunch with Jim Landis, who had approved the purchase of the book.

Jim Landis is the same J.D. Landis who approved the purchase of Zen and the Art of Motorcycle Maintenance. When she said Jim Landis, I almost wet myself. I couldn’t believe it was the same Jim Landis who took a chance on Pirsig’s book.

We spent half the lunch talking about The Insulin Connection, a title they hated. They didn’t like the title, because at that time insulin resistance was known only in the scientific literature. They thought potential readers who might be buyers of the book would think it was just about diabetes, and everybody in publishing at the time knew books about diabetes didn’t sell.

The other half of the lunch was occupied with my peppering Landis about why be bought Zen and a thousand questions about Pirsig. It was the best publisher’s lunch I’ve ever been a part of, and there have been quite a few.

According to Gioia, Zen has sold ~5 million copies. Protein Power has sold about 80% of that number, so Landis picked at least two good ones. Unfortunately, William Morrow did not end up publishing what became Protein Power. Our editor, who had bought the book at Morrow, left for another publishing job. And so did Landis. For reasons too numerous to discuss here, when an editor leaves, it is a disaster for any of the books he/she has in production.

Our editor ended up selling Protein Power to Bantam Books. I hated to leave Morrow, but our agent told us we had to.

If you look at a Venn diagram of our publishing career and Robert Pirsig’s, there is very little overlap.

But there is some tiny bit of overlap, a tiny sliver of a place where our paths intersect, which makes me ecstatic since I loved Pirsig’s book so much.

When Fat Cells Run Out of Oxygen. A Hidden Driver of Infection Risk

I just finished reading a paper in Lancet on how obesity leads to infection. And about how many obese people die of infectious diseases. The paper makes for pretty grim reading, especially for anyone carrying a lot of excess weight in the form of fat.

Reading the paper got me thinking about why excess adipose tissue causes inflammation. Let’s take a deeper look.

The Lancet article makes something perfectly clear: people living with obesity face dramatically higher risks of being hospitalized or dying from infections of nearly every kind – bacterial, viral, fungal, and parasitic. But it really doesn’t make clear why carrying excess body fat would make someone so much more vulnerable to such a plethora of infectious diseases?

I don’t think the answer lies in the infections themselves, but in what is happening deep inside the fat tissue long before any pathogen arrives.

Adipose (fat) tissue is not simply an inert storage depot for excess calories.

Adipose tissue comes in two denominations: subcutaneous adipose tissue and visceral adipose tissue. Subcutaneous adipose tissue (SubQ) is the storage form of energy. SubQ is where we store the excess energy we consume so that is available for our needs when we need it.

Visceral adipose tissue (VAT) is where we put excess fat when the SubQ volume is filled.

SubQ fat is primarily determined by our genetics, which is why people in the same family often have more or less the same body habitus. Some of us have a lot of SubQ space, while others not so much.

If we use the metaphor of the home, we can think of SubQ fat as all the usual storage places we have: attics, garages, basements, closets, etc. If we’re hoarders, we fill up those spaces first, while keeping the part of the home visible to guests spic and span. But once we run out of storage places for our junk, continued hoarding means we end up with junk in the living part of the home.

It’s the same with SubQ fat. We stick our fat there first, but when we run out of SubQ space, the only place left for fat to go is to the viscera. And that is a dangerous place for it to be, because it doesn’t belong there. When fat starts infesting the viscera, the body treats it as a foreign body the same way it does a splinter in a finger. Macrophages — the body’s cleanup crew — move in to try to deal with the fat that isn’t supposed to be there.

(Note: The genetic difference in the individual amount of SubQ space is why different people are more prone to, say, diabetes than others. An individual with a lot of SubQ space can pack a lot more fat into the basically more harmless storage area than can one with not so much SubQ space. Which is why some thinner people with less SubQ storage space might develop type II diabetes, whereas one with a lot of SubQ space might become obese, but not so prone to type II diabetes, which is pretty much a function of visceral fat.)

When macrophages move in, they send ‘help’ signals out to other macrophages. Those other macrophages heed the call and come to help. As visceral fat continues to accumulate, as in the stepwise progression shown above, so many macrophages enter the fray that the mass of the fat can be composed of anywhere from 50 to 60 percent macrophages. (Seen also in the actual photomicrograph below of macrophage infiltration (the brown things) of adipose tissue. The asterisk marks a lipid droplet in a fat cell.)

If you get a splinter in your finger, your finger becomes inflamed. If the splinter has been in there long enough – and it doesn’t take a long time – when you try to get it out, it often flows out in a trickle of pus. Gross as it sounds, that is similar to what is happening in your visceral fat. I’ve used the graphic below of a belly full of visceral fat likened to a splinter.

Why does all this happen?

Fat cells are living, metabolically-active tissue requiring a steady supply of oxygen and nutrients delivered through a network of tiny blood vessels. Under normal circumstances, this network is adequate for the job. But when fat cells expand dramatically in size during the development of obesity, they eventually grow too large and too numerous for their existing blood supply to keep up. In other words, they outgrow their blood supply. Unlike with SubQ tissue, there is no restraint to growth with visceral fat. Which is why there are a lot of skinny people with big, fat bellies.

When fat cells outgrow their blood supply, a portion of the adipose tissue is left deprived of oxygen, a condition known as hypoxia or oxygen starvation. Fat cells don’t quietly accept this oxygen shortage. Instead, they sound an alarm.

The key alarm signal is a protein called HIF-1α, short for hypoxia-inducible factor 1-alpha, which is a truly fascinating protein.

HIF-1α is what is called a constitutive protein, which means it is produced constantly. The gene that codes for it constantly sends the signal for its production. Once produced, HIF-1α sticks around for only a few minutes, then is targeted and deactivated by an enzyme called prolyl hydroxylase.

Protein production in the body is an energetically expensive process, so the fact that HIF-1α is produced and degraded constantly must provide some huge survival benefit.

As it turns out, it does indeed.

Under normal oxygen levels, the body continuously destroys HIF-1α almost as fast as it is made, keeping it from accumulating. But when oxygen runs low inside the swelling fat tissue, this destruction process shuts down, and HIF-1α begins to build up inside the cell. Once it accumulates, HIF-1α moves into the cell's nucleus and begins switching on a large set of genes involved in inflammation–essentially triggering an emergency response throughout the fat tissue.

The trigger for blocking the destruction of HIF-1α shows just how nifty this whole process is.

In other issues of The Arrow we’ve talked about the electron transport chain that resides in the mitochondria, the energy-producing organelles inside all our cells. (Like other cells, the fat cells contain thousands of mitochondria.) The two energy-producing systems within the mitochondria are the electron transport chain (ETC) and the Krebs cycle (also called the TCA cycle). The one direct physical connection both have is Complex II, which is the only part of the Krebs cycle that is also a part of the ETC. Complex II acting as part of the Krebs cycle converts succinate to fumarate. When the mitochondria suffer an oxygen loss, the process stops working efficiently, and succinate begins to back up. It is this backup of succinate that triggers the process that impairs the breakdown of HIF-1α.

(I’m sorry, but that’s the best graphic I could find of the Complex II-Krebs cycle connection.)

So a backup of succinate indicates a shortage of oxygen, which leads to the HIF-1α being free to do its job, which is to increase the inflammatory response.

HIF-1α: The Emergency Manager That Goes Rogue

In a healthy, short-term oxygen shortage – say, during intense exercise or at high altitude – HIF-1α activation is genuinely helpful. It tells cells to switch their energy production from pathways that require oxygen over to glycolysis, another way to make ATP, but without oxygen. It also tells the body to make more red blood cells and grow new blood vessels to compensate for the deficit. It's a clever, elegant adaptation.

But in the context of chronically-expanding, oxygen-starved fat tissue, HIF-1α's activation isn't short-term. It becomes persistent. And its downstream effects, which were designed for emergencies, become destructive when they run continuously.

Critically, HIF-1α in fat cells with low-oxygen levels (hypoxia) also commands them to release a flood of chemokines and cytokines – chemical alarm signals that summon immune cells. Chief among these is a molecule called MCP-1 (monocyte chemoattractant protein-1). This molecule is basically a biological "come here" signal for circulating monocytes, a type of immune cell that can transform into an inflammatory macrophage once it arrives in a tissue. Thus the aforementioned glut of macrophages.

To make things even worse, the process being driven by HIF-1α in the fat cells makes the tissue physically stiffer. Stiff tissue limits the ability of fat cells to expand in a healthy, controlled way. This pushes the system toward more stress, more hypoxia, more HIF-1α activation. The fat tissue becomes trapped in a vicious cycle.

But it gets even worse.

The inflammatory cytokines pouring out of hypoxic fat tissue don't just hang around in the fat tissue. They enter the bloodstream and travel to organs throughout the body. In the liver, muscle, and even in other fat depots, these cytokines including IL-1β, TNF-α, and IL-6 interfere with insulin signaling. Specifically, they disrupt a critical cellular relay known as the IRS-AKT pathway, the molecular chain of events that normally allows insulin to tell cells to take up glucose from the blood. When that signal is jammed, cells become resistant to insulin.

Over time, this progression creates a state of chronic, low-grade inflammation that never fully resolves. And here lies the connection to infection risk. The immune system, perpetually engaged in managing this background inflammatory fire sparked by oxygen-starved fat cells, becomes less capable of mounting a sharp, focused response when a real pathogen shows up. Key immune cells – including those responsible for recognizing and destroying bacteria and viruses – become less functional in this chronically inflamed environment. The body is occupied fighting one battle and therefore less prepared to fight another.

Which helps explain why the increased infection risk detailed in the Lancet paper spans such a broad range of pathogens.

It is not that obesity creates a specific vulnerability to one type of infection. Rather, the HIF-1α-driven inflammatory response triggered by hypoxic fat tissue causes a generalized weakening of the body's defenses, leaving individuals with obesity more exposed across the board. Understanding this cellular chain of events, from expanding fat cells, to oxygen deprivation, to HIF-1α activation, to chronic inflammation, to impaired immunity, points toward a coherent biological explanation for a real public health issue, i.e., the increase in death rates of the obese from infection. We saw it writ large during Covid, but it didn’t stop there.

The Takeaway

Stepping back, the point of this post is not to induce fatalism, but to make the biology legible enough that one can do something about it. If hypoxic, inflamed visceral fat is one of the central levers increasing heightened infection risk, then anything that safely reduces visceral adiposity or improves adipose oxygenation – from weight loss and improved fitness to better sleep and metabolic health – is not merely “cosmetic,” but rather a crucial immunological intervention. Framed this way, efforts to prevent and treat obesity are not just about aesthetics or even reducing cardiometabolic risk (though that’s important as well); they are about giving the immune system back the bandwidth it needs to fight the infections that, as the Lancet paper shows, are claiming far too many lives.

It should go without saying, particularly to readers of The Arrow, that the best way to lose weight and improve metabolic function is to go on a whole food low-carb/ketogenic diet and engage in regular resistance exercise.

Odds and Ends

• According to Consumer Reports, the most expensive and least expensive grocery stores in the United States.

• World's rarest primate makes a comeback.
  
  Well, they left the Seymour, MO Apple Festival and the Carpinteria, CA Avocado Festival off the list, but there are some interesting small town festivals here. Especially the one in Colorado, which I confess, though we lived not far away for a time, we never made it to.
  
  Why do humans have chins and other apes do not? Not sure I agree with the conclusion the authors reached but it’s an interesting thing to think about.

• The reading statistics for people in the United States are grim indeed.

• Places and times where and when coffee drinking was illegal. You could have been executed were you caught drinking it. I’d be on the run!

• What happens when social media feeds challenge your political views instead of reinforcing your confirmation bias.

• The dark side of wolf reintroduction.

• Scientists uncover first evidence that the Romans deployed human feces as medicine. For fecal transplants, not to eat. Everything old is new again.

• Fossils of huge 'hell heron' dinosaur unearthed in Niger. Scroll down to see the photo of the giant skull. Truly impressive.

• Japanese researchers discover chronic “bacterial constipation,” a new disease caused by gut-drying bacteria.

• Three 'odd' thinking patterns are consistently linked to higher intelligence.

• Paleontologists know it as Andrewsarchus mongoliensis, and after decades of mystery, they’re still working to piece together the true nature of this giant carnivore.

• Reese's inventor's grandson says its new candy Is 'not edible.'

• Pompeii's house of Dionysian delights contains vivid frescoes in an opulent dining room celebrate the wild rites of the wine god.

• The Labyrinth at Hawara: What the scans found and why Egypt won’t let anyone dig.

• A centuries-old sword from the time of the Crusades was discovered by a student swimming off the coast of Haifa, Israel.

• A British explorer’s quest to reach all the middles of nowhere. But why would anyone want to go there?

• Something was making stone tools in China 600,000 years before Homo erectus showed up. Or, are we misdating Homo erectus?

• It’s called the ‘Fitbit for Farts’—and it’s no joke. Scientists developing a new underwear-able hope to do for gastroenterology what the Apple Watch did for cardiology.

Newsletter Recommendations

Video of the Week

This video popped up on MD’s feed recently and she was amazed and horrified all at once. It is amazing, And in its weird way beautiful, I’ll admit. But kind of scary because what goes up must come down. Could it be that in a few years (or more), we’ll be bombarded with space waste?

Time for the poll, so you can grade my performance this week.

That’s about it for this week. Keep in good cheer, and I’ll be back soon.

Please help me out by clicking the Like button, assuming, of course, that you like it.

This newsletter is for informational and educational purposes only. It is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment and should never be relied upon for specific medical advice.

Thanks for reading all the way to the end. Really, thanks. If you got something out of it, please consider becoming a paid subscriber if you aren’t yet. I would really appreciate it.

Finally, don’t forget to take a look at what our kind sponsors have to offer: HLTH Code, Precision Health Reports, and Jaquish Biomedical.

And don’t forget my newest affiliate sponsor Lumen. Highly recommended to determine whether you’re burning fat or burning carbs.