Everything You Know About Thrifty Genes Is Wrong — 6

Very recently (October 2022) a paper was published with the daunting title, “The PPARGC1A Is the Gene Responsible for Thrifty Metabolism Related Metabolic Diseases: A Scoping Review.” It contains intriguing information for those who are interested in this sort of thing.

To verify its credentials, a thrifty gene can contribute to the regulation of energy balance, or it can work with metabolism or other physiological functions. A meta-study revealed that despite some inconsistent results, it appears that PPARGC1A Gly482Ser is the gene responsible for thrifty metabolism in the earth’s Pacific population. The paper states,

Positive selection of gene alleles associated with specific traits, such as obesity as a predisposing factor for non-communicable diseases, supports the thrifty gene theory hypothesis in terms of genetic susceptibility.

Differences in the prevalence of metabolic diseases in the population resulted from the frequency of polymorphisms and different risk alleles between populations.

The paper’s introduction provides several provocative statements:

The thrifty gene hypothesis can be understood in two forms: thrifty early and thrifty late. The thrifty early form corresponds more closely to Neel’s perspective, whereas the thrifty late form is the more common view among geneticists.

Genetic variations in genes related to metabolic diseases, especially diabetes mellitus, are considered to be candidates for thrifty genes in the population.

The brain runs on glucose, and in this worldview, the brain’s survival is a top priority. To get its fix, the brain has to make the body eat, and hold onto stored energy. In the past, a purpose was served. But nowadays, all that bogus energy, generated from ingredients with varying degrees of toxicity, is widely available and widely consumed. The authors say, “[I]ncreasing adiposity can induce a state of persistent low-grade inflammation and hence activate the insulin resistance pathways.” There’s more:

Diabetes as a multifactorial disease is thought to be a description of the failure of adaptation of gene alleles to current environmental conditions compared to previous conditions, thus, a wide variety of metabolic syndrome manifestations are associated with the response to these changes.

Adaptability is an awesome trait, but it can be either beneficial or detrimental. An adaptation that sticks around too long might find itself superseded and outmoded. An adaptation that benefits one organ or system at the expense of others is not the best answer. When too much glucose comes in and hangs around for too long, it would seem that further adaptation is called for. Part of the brain needs to tell the other part to slow its roll.

Your responses and feedback are welcome!

Source: “The PPARGC1A Is the Gene Responsible for Thrifty Metabolism Related Metabolic Diseases: A Scoping Review,” NIH.gov, 10/13/22
Image by Aloizio Mercadante Oliva/CC BY-SA 2.0

Everything You Know About Thrifty Genes Is Wrong — 5

Scholars who retain an interest in Dr. James V. Neel’s thrifty gene hypothesis have been disappointed time and again, by finding candidates that did not measure up to the criteria. “The evidence for a specific gene alteration generating a thrifty genotype is inconclusive,” writes oncologist Ajit Venniyoor, who then proposes PTEN as the gene that appears to influence metabolism, cancer, and reproduction.

What those areas have in common is, they become “deranged in obesity and insulin resistance.” The author goes on to explain that the gene is “like a metabolic rheostat” which “fixes’ the metabolic capacity of the organism periconceptionally to a specific postnatal level of nutrition, but when faced with a discordant environment, leads to obesity related diseases…” It sounds like what Dr. Neel was talking about, to the point where Dr. Venniyoor concludes that “PTEN is the primary thrifty gene.” Here is the extended, technical reasoning:

Epigenetic modification (methylation) of PTEN promoter suppresses the expression of the gene proportional to availability of nutrients (protein, and possibly choline). This sets the metabolic capacity and adapts the fetus to nutrition availability in post natal environment. A mismatch with calorie abundance results in efficient storage and limited expenditure and causes obesity, metabolic syndrome and cancer.

This gene can make good use of limited energy to grow and reproduce. It arranges for the safe storage of excess energy, and “multiple lines of evidence suggest that PTEN does this brilliantly.” In short, it fits the thrifty gene job description.

Skeptics say that a gene or genes like the one Dr. Neel visualized would eventually lead to the extinction of humans with non-thrifty genotypes. We haven’t all died yet, but an awful lot of metabolic diseases are looking to kill us, and the thrifty genotype hypothesis is seen as providing an explanation for that. Author Kian-Peng Goh points out the disadvantage such a genotype would suffer when faced with “dissonance between ‘Stone Age’ genes and ‘Space Age’ circumstances”:

However, no thrifty genes or variants have been identified to date and only approximately 20%-30% of the population is obese, although one would expect a proportion close to 100% since according to this hypothesis, everyone should have thrifty genes by now. Consequently, the debate on thrifty genes still rages on.

Your responses and feedback are welcome!

Source: “PTEN: A Thrifty Gene That Causes Disease in Times of Plenty?,” FrontiersIn.org, 06/05/20
Source: “Gene–Environment Interaction in the Pathogenesis of Type 2 Diabetes,” ScienceDirect.com
Image by Diego Mundarain/CC BY-ND 2.0

Everything You Know About Thrifty Genes Is Wrong — 4

We saw how Dr. James V. Neel’s thrifty gene hypothesis led to much speculation and inspired other researchers to rethink some of their ideas, and also how the theory gained unsavory political dimensions.

Neel’s original ideas were upheld by nutritionist Andrew Prentice, who wrote a lively response to the “drifty gene hypothesis” proposed by biologist John Speakman which, among other things, did not see obesity as having any selective advantage, ever. Their competing arguments were published together in the International Journal of Obesity in November 2008. There have been at least four “waves” of genome-wide studies concentrating on obesity, so it’s not as if the idea of genetic responsibility is absurd.

So, the “drifty gene hypothesis” drew some attention, and at the same time, the “thrifty phenotype” idea also sounded likely. Type II diabetes grew more prevalent and revealed that multiple genes and body systems are involved in the disease.

Childhood obesity points the way

An article by Robert H. Lustig, M.D., and Ram Weiss, M.D., noted that the association between obesity and genetics stemmed from two distinct lines of investigation, “the discoveries of monogenic disorders of the energy balance pathway […] and studies of specific racial and ethnic groups, in which obesity seems to segregate…,” and went on to say,

These observations are combined with an attractive theory on the natural selection of individuals in response to drastic environmental/ecologic pressure (i.e., famine), termed the thrifty gene hypothesis, to yield a very strong driving force for the elucidation of specific genetic loci in the pathogenesis of obesity. However, the rapid timescale of the increased prevalence of childhood obesity cannot possibly reflect a population genetic change. Therefore, the current model is that obesity is a result of gene-environment interactions…

Although widely contested, the thrifty gene concept has refused to lie down and die. Its 80-year history was traced in a thesis written earlier this year by Grayson James Hughes of the University of Arizona, who found that although the thrifty gene hypothesis does not exactly align with what has since been discovered about type II diabetes, the theory has nevertheless provided important insights, and informed many aspects of research into the disease. He says,

The review ends with the more promising idea of the thrifty phenotype, originally proposed by Barker and Hales and with the increased levels of type II diabetes still present in modern society… New avenues of research into childhood environment showed evidence for a thrifty phenotype hypothesis that has garnered more evidence and support in recent years.

Only three months ago a thesis paper was published with the title, “Immorality of the Thrifty Gene: moral and epistemic applications of genetic paleofantasies in weight-focused behavioral therapy.” Author Ana Lucia Battaglino is very interested in how weight-management medicine specialists think about such controversial topics as natural hunger, metabolic homeostasis, and human evolution “in a clinical approach to behavioral intervention called Acceptance-based Behavioral Therapy (ABT).” She asks,

How do clinicians teach patients to respond to their “thrifty genes,” or the human body’s genetic tendency towards fat accumulation? What affective relationships to food, eating, and the human body are invoked by the practices of medically supervised weight loss?

Your responses and feedback are welcome!

Source: “The Metabolic Syndrome at the Beginning of the XXI Century,” ScienceDirect.com, 2005
Source: “Disorders of Energy Balance,” ScienceDirect.com, 2008
Source: “The Thrifty Gene Hypotheses: A Total Review,” Arizona.edu, 2022
Source: “Immorality of the Thrifty Gene,” UChicago.edu, 08/23/22
Image by Oak Ridge National Laboratory/CC BY 2.0

Everything You Know About Thrifty Genes Is Wrong — 3

The previous post referenced a thesis published by Grayson James Hughes earlier this year in Epidemiology of Diabetes. This paper restated the persistent, inexplicable, and nearly universal problem of recidivism (personal failure) in efforts to control obesity:

Put very simply, it is as if early in life an insistent and demanding biological drive to consume more calories than is appropriate to maintain normal body weight was established, and although this drive can be temporarily abrogated, it almost irresistibly reasserts itself.

Dr. James V. Neel, known for his thrifty gene hypothesis, referred to this regulatory phenomenon as a “calorie-stat” that is set by an as-yet unknown power. Also, he asserted that figuring out this one mystery is the most important priority in obesity studies.

Currently, a quotation credited to Brené Brown is popular, if controversial: “Science is not the truth. Science is finding the truth. When science changes its opinion, it didn’t lie to you. It learned more.” Dr. Neel was convinced that many answers still awaited discovery. It’s not as if he was some kind of lone madman. Despite many objections to his theory, there was also agreement in some quarters, and in others, a continuing, if grudging, partial or conditional acceptance.

A lot of maybes

As time went on, new obesity-related gene variants were identified, but none possessed identifiable properties that could really be said to confer any survival advantage, or to qualify as the elusive thrifty gene. Yet there did seem to be a “thrifty phenotype.”

In 2018 the Encyclopedia of Endocrine Diseases said,

A large number of studies in animals and humans linked poor prenatal nutrition with subsequent predisposition to disease, including obesity later in life and in subsequent generations.

The debate took on another dimension when Canadian researchers picked up on the thrifty gene, and racism entered the picture in a big way. James Daschuk wrote that accepting an inherent genetic vulnerability by which Indigenous people were predisposed to diabetes, enabled politicians and administrators to…

[…] explain away the disease’s explosion among Indigenous people. It allowed the same officials to continue to ignore the ongoing social realities at the root of Indigenous diabetes, namely: the deleterious impact of historically racist federal policies that entrenched food insecurity, poverty and ill-health within Canada’s Indigenous communities.

A similar paper by Robyn McDermott began with some patently militant statements like,

[This paper] looks at some of the ethical consequences of the biological deterministic paradigm, particularly the popular confusion of “genes” with “race” and how this paradigm served to exclude consideration of social determinants of disease in epidemiological thinking.

Like Daschuk, he was very much in favor of looking at alternative hypotheses to the thrifty gene theory, if they would minimize the possibility of hostile political manipulation and improve the outlook for public health consequences.

Your responses and feedback are welcome!

Source: “The Epidemic and Prevalence of Diabetes in the United States,” ScienceDirect.com, 2019
Source: “The Thrifty Gene Hypotheses: A Total Review,” Arizona.edu, 2022
Source: “Atlas of the Heart Quotes,” Goodreads.com, undated
Source: “Encyclopedia of Endocrine Diseases,” ScienceDirect.com, 2018
Source: “Travis Hay, Inventing the Thrifty Gene: The Science of Settler Colonialism,” OUP.com, 2021
Source: “Ethics, epidemiology and the thrifty gene: biological determinism as a health hazard,” November 1998
Image by JoslynLM/CC BY 2.0

Everything You Know About Thrifty Genes Is Wrong — 2

The previous post explained Dr. James V. Neel’s thrifty gene hypothesis and the notion of “starvation mode” that grew from it.

Pushback and rethinking

Neel’s original thrifty gene hypothesis received various criticisms, some of which could be attributed to plain old common sense, with no scientific training required. For instance, because of all the fruits and fish so easily available to them, Pacific Islanders and similar populations have not historically experienced famine or starvation. So they had no need for thrifty genes — and yet tend to be quite fleshy. Also, there are contemporary hunter-gatherer populations who do not accumulate large bodily fat stores between famines. It was also pointed out that in a time of famine, death occurs mainly from infection, rather than loss of adipose tissue.

It became evident that the thrifty genotype hypothesis was over-simplified, yet could not be completely abandoned. Consequently, other researchers and Dr. Neel himself proposed modified or alternative hypotheses. He published a revisionist look at his previous work, and an expanded form of the original idea that called for…

… a more complex theory of several related diseases such as diabetes, obesity, and hypertension (see also metabolic syndrome) being caused by physiological systems adapted for an older environment being pushed beyond their limits by environmental changes.

He still believed that the “thrifty genotype” concept was viable, and had some other things to say about it in relation to non-insulin-dependent diabetes mellitus (NIDDM), such as:

[W]hy is the predisposition to NIDDM so frequent? Explanations based on the “thrifty genotype” hypothesis continue to be invoked. Over the past 35 years, it has become increasingly clear that essential hypertension and obesity share many of the epidemiological features of NIDDM. Both are diseases of civilization, with a very gradual onset.

In 2008, it was proposed that Dr. Neel’s theory “may provide an evolutionary basis for genetic predisposition to Metabolic Syndrome…” Dr. Neel had originally said that obesity-prone animals could survive through famines better than animals that did not, in good times, tend toward obesity. And sure enough, experiments showed that mice who are genetically prone to obesity actually could withstand prolonged food deprivation better than slimmer kinds of mice. This became interesting when science started to identify genes that predispose humans to Metabolic Syndrome.

Clues?

A recent thesis by Grayson James Hughes that was published by the University of Arizona notes that by the early 2000s “there were five subtypes of diabetes identified in younger patients, each containing distinct insulin resistances and different genetic causes.” One of the elaborations on Dr. Neel’s original thought was dubbed the “thrifty phenotype” hypothesis, having to do with malnutrition in newborns that could lead to flawed insulin production. Here is a description of that phenomenon, originally published in Epidemiology of Diabetes:

[T]he thrifty phenotype hypothesis or fetal origins hypothesis suggests that poor nutrition during fetal development will lead to restricted intrauterine growth, as well as phenotype changes. These changes include low birth weight and body size, reduced metabolism, and alterations of glucose-insulin metabolism that will likely cause nutritional problems in later life.

And Dr. Neel himself still believed that there was somehow more to all this than met the eye.

(To be continued…)

Your responses and feedback are welcome!

Source: “The ‘Thrifty Genotype’ in 1998,” UMich.edu, 1999
Source: “Factors that contribute to metabolic syndrome,” ScienceDirect.com, 2008
Source: “The Thrifty Gene Hypotheses: A Total Review,” Arizona.edu, 2022
Source: “The Epidemic and Prevalence of Diabetes in the United States,” ScienceDirect.com, 2019
Image by Brendan/CC BY 2.0

Everything You Know About Thrifty Genes Is Wrong

The thrifty gene hypothesis, introduced in 1962 by James V. Neel, M.D., Ph.D., originated as an effort to explain diabetes, and then expanded to potentially account for obesity as well. (He later noted that this paper was written “before the clear distinction between type I and type I1 diabetes had been drawn, but in retrospect it was directed at type II.”) Dr. Neel defined thrifty as “exceptionally efficient in the intake and/or utilization of food.” The provocative paper suggested ways to test the hypothesis, and the through line boiled down to:

In this essay an hypothesis has been advanced which envisions diabetes mellitus as an untoward aspect of a “thriftiness” genotype which is less of an asset now than in the feast-or-famine days of hunting and gathering cultures.

In the late 1960s, people thought this sounded likely, and that type II diabetes had a genetic origin, though nobody could pinpoint the exact genes involved. The prevalence of such a gene or genes could have occurred in order to survive intermittent starvation. The idea that humans might be genetically hardwired to accumulate body fat and then hold onto it made a certain amount of sense, because throughout most of history, food insecurity was the norm for just about everyone.

Outsmarting decay

In the old days, salt and spices were incredibly valuable because they preserved food. The existence of, and trade in, spices made it somewhat easier to alleviate the ravages of famines caused by weather, enemy action, and the like. Several gigantic advances in human ingenuity had to happen before we could know the confidence that comes from having a stash of canned goods in the basement.

But, according to Neel’s theory, genetic progress did not keep pace, and humans are still under the influence of a genotype that wants to prepare us for a famine that we will never actually experience. (While this may be true of the majority of people in developed countries, such confidence is certainly not universal.)

The thrifty gene hypothesis proposed that one of the chief survival instincts is the imperative to absorb whatever food is available, in order to store fat so the body has energy to burn when times are hard and food is scarce. Also, that another survival instinct is based on built-in safeguards that prevent the body from letting go of that stored fat. One of the details is a belief that trying too hard to lose weight, by limiting caloric intake, can actually have the opposite effect, by sending the body into “starvation mode” which makes it try even more desperately to conserve its stored fat.

Starvation a la mode

A fitness guru known as Jay, whose work has appeared in at least a dozen major publications, explains the thinking behind the starvation mode school of thought:

[T]he fundamental concept behind what causes starvation mode is this: Being in too much of a caloric deficit is supposedly capable of stopping weight loss. When you eat too little and/or burn too much, your body’s survival response is to hold on to all of your fat and slow your metabolism enough to prevent you from losing anything (or potentially even cause you to gain additional fat).

Jay says there is no such thing as “starvation mode,” and that a caloric deficit always produces weight loss. There is, however, such a thing as adaptive thermogenesis, meaning that the metabolism does slow down during weight loss — but adaptive thermogenesis is never influential enough to either stop weight loss, or to cause weight gain.

(To be continued…)

Your responses and feedback are welcome!

Source: “Diabetes Mellitus: A ‘Thrifty’ Genotype Rendered Detrimental by “Progress”?,” NIH.gov, 1962
Source: “Starvation Mode: Is It A Myth?,” AWorkoutRoutine.com, 11/19/22
Image by Esteban Chiner/CC BY-SA 2.0