Being overweight or too thin are clues as to what might be going on “under the hood.”
After this post, I will have listed over 136 biological mechanisms of weight modulation.
See the following posts, which have 62 different unique mechanisms than what’s listed below:
- A First Principles Approach To Obesity/Anorexia: The Big 4 Hormones
- 27 Hormones Involved in Weight Problems (not big 4)
- 31 Scientific Ways That Inflammation Can Change Your Weight
Sometimes, it’s not clear whether something causes weight gain or weight loss, but I simplify it. Other times, it’s not clear what the overall impact is.
CART causes weight loss.
Cocaine- and amphetamine-regulated transcript (CART) is a natural stimulant that has roles in pleasure, eating, and stress .
CART is a neuropeptide that produces similar behavior to cocaine and amphetamines, including increased physical activity and a positive feeling .
CART has been shown to suppress food intake, like cocaine and amphetamines (when injected into the 4th ventricle of rats and in nodose ganglia) .
Mice without CART genes prefer alcohol less , which implicates CART in alcoholism.
CART is also increased by cocaine and amphetamines , but obviously, the risks outweigh the benefits if just used for weight loss.
Opioids cause weight gain.
Opioid blockers (naloxone) reduces appetite .
Activating opioid receptors promote eating and weight gain, at least in the short term .
When fed a high-fat diet, mice without mu-opioid receptors were resistant to obesity, despite having similar calorie intake to normal mice fed a high-fat diet. This resistance to obesity with the mutant mouse without mu-opioid receptors was associated with increased fatty acid oxidation within the muscle .
When food proteins are digested, they produce peptides that block mu-opioid activity.
These peptides are released in the vein that brings blood flow to the gut. The vagus nerves communicate with the brain initiate satiety as a result of the mu-opioid blocking (as a result of sensing gut gluconeogenesis) .
This is one reason why a protein-rich diet aids in weight loss.
When the mice were switched from a starch- to a protein-enriched diet, mice reduced their food intake by about 20%, but no such effect occurred in the mice lacking the mu-opioid receptors .
3) Nicotinic Receptors
Nicotinic receptors cause weight loss.
The hypothalamus is rich in cholinergic neurons and has some of the highest levels of nicotinic receptors in the brain .
Nicotine excites mouse hypothalamic POMC neurons and inhibits MCH (via increasing GABA), both of which inhibits appetite. Nicotine increases serotonin and dopamine, which also helps with appetite. Nicotine actually increases NPY (appetite stimulant) but decreases its receptors .
Other effects of nicotine might be to reduce inflammation in fat cells, which causes weight loss .
4) Dopamine (in the hypothalamus)
Dopamine causes weight loss.
People with genetically fewer dopamine D2 receptors needed to consume more of a rewarding substance (such as drugs or food) to get that same effect .
When mice were treated with a molecule that selectively activates DRD2, they exhibited anorexia .
Dynorphin causes weight gain.
A number of studies in rats have shown that increasing the dynorphin levels stimulates eating .
Dynorphin is increased by stress, which is one reason why stress causes weight gain in some people.
Animal studies revealed that dynorphin increases in aged rodents and causes impairment of memory function.
Increased Dynorphin A levels have been observed in the brains of Alzheimer’s disease patients. In addition, it was shown that dynorphin reduces long-term potentiation at hippocampal synapses, synaptic transmission and neural plasticity .
(Dynorphin produced in the arcuate nucleus and in orexin neurons of the lateral hypothalamus affects appetite.)
AMPK causes weight gain, overall, although the effects are tissue specific.
AMPK activation in the Arcuate nucleus increases food intake .
AMPK has different effects on weight.
The net effect of AMPK activation is weight gain (lipogenesis, triglyceride synthesis, inhibition of adipocyte lipolysis) .
A recent paper on mice at Johns Hopkins has shown that when the activity of brain AMPK was inhibited, the mice ate less and lost weight. When AMPK activity was raised, the mice ate more and gained weight .
Metformin is an AMPK activator that usually causes weight loss and reduced appetite, not weight gain and increased appetite. This is because it decreases AMPK in the hypothalamus .
The effects of AMPK depend on the tissue, even the tissue in the brain.
AMPK activation in the muscle seems to help burn fat, and this is one mechanism by which leptin causes weight loss .
R-Lipoic Acid is a way to decrease hypothalamic AMPK.
Compounds and Signals that Affect Hypothalamic AMP-Activated Protein Kinase (AMPK) Activity.
|Appetite increasers (activators of hypothalamic AMPK)||Appetite suppressors (inhibitors of hypothalamic AMPK)|
|Hypoglycemia, 2-deoxyglucose (14–17)||Glucose (11, 14)|
|Agouti-related peptide (11)||Leptin (11)|
|Ghrelin (12, 27)||Insulin (11)|
|Cannabinoids (27)||C75 (46)|
|Glucocorticoids||α-Lipoic acid (14)|
|Adiponectin (42)||Metformin (17)|
|Low temperatures (53)||Ciliary neurotrophic factor analog (20)|
|Thyroid hormones (50)||α-melanocyte-stimulating hormone, MT-II (a melanocortin 4 receptor agonist) (11,73)|
8) Hormone-Sensitive Lipase
Hormone-sensitive lipase causes weight loss.
The main function of hormone-sensitive lipase is to mobilize stored fats , which has the effect of making you thinner.
Hormone-Sensitive Lipase is the rate-limiting step for breaking down fatty acids from the triglyceride molecules .
Another important role is the release of cholesterol (from cholesterol esters) for use in the production of hormones .
cAMP is activated by adrenaline and ACTH .
Exercise and a low carb diet may help.
Perilipin causes weight gain.
Perilipin is elevated in obese animals and humans .
In mice, perilipin increases food intake, but helps lower fat levels and increase muscle mass with the same number of calories .
Mice without perilipin have enhanced leptin production and a greater tendency to develop insulin resistance .
Polymorphisms in the human perilipin (PLIN) gene have been associated with variance in body-weight regulation and may be a genetic influence on obesity risk in humans .
10) Atrial natriuretic peptide (ANP)
ANP causes weight loss.
ANP increases the release of free fatty acids from fat tissue .
Obese patients had significantly lower B-type natriuretic peptide (p = 0.03) and atrial natriuretic peptide (p = 0.04) levels compared with nonobese.
Low levels of circulating natriuretic peptides are thus associated with obesity and may also contribute to the development of heart failure .
ANP increases cGMP levels, which induce hormone-sensitive lipase and perilipin A .
ANP is a powerful fat busting agent, independent of the activation of the fight or flight nervous system, in both lean and obese people .
Other information on ANP:
Atrial natriuretic peptide (ANP) is a powerful vasodilator .
ANP relaxes our blood vessels and decreases blood volume, which lowers blood pressure .
ANP has exactly the opposite function of the aldosterone in regard to its effect on sodium in the kidney – that is, aldosterone stimulates sodium retention and ANP generates sodium loss. ANP inhibits aldosterone release .
Exercise and stress reduction can help increase ANP.
ANP is secreted in response to :
- Stretching of the atrial wall.
- Reduced sympathetic stimulation of β-adrenoceptors
- Raised sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion
- Endothelin, a potent vasoconstrictor
11) Fat mass and obesity-associated protein (FTO)
Overall, FTO seems to cause weight gain.
FTO seems to have different effects based on the tissue in which it’s found.
There’s FTO in fat cells, in the hypothalamus and in specific parts of the hypothalamus.
In fat cells, FTO can cause weight gain.
FTO could inhibit the “browning process” of white fat tissue. FTO inhibits the uncoupling protein 1 (Ucp1), which turns white fat to brown fat .
When mice had their FTO gene deleted, their fat cells were smaller on a high-fat diet .
The leanness of the FTO-deficient mice is a consequence of increased energy expenditure .
The capacity of white fat cells to become enlarged is a key factor in the cause of excessive weight gain. The size of the white fat cell is highly correlated with its capacity to become insulin resistant and also with the level of inflammation .
It seems that when FTO is missing from the beginning, it has different effects and fat cells are smaller. Whereas at a certain stage, if FTO decreases, it’s too late .
Some of the effects of FTO might result from its long-range regulatory alteration of another gene: Irx3 .
Inactivation of the FTO gene impairs dopamine receptor type 2 (D2R) and type 3 (D3R) .
INSIG2 causes weight gain.
INSIG2 (but not INSIG1) is predominant in fat creation, with a marked increase in gene expression during fat cell creation .
INSIG2 gene is associated with obesity . A large genetic association study showed evidence for SNP rs7566605 with obesity in several cohorts . INSIG2 gene was consistently associated with increased BMI .
INSIG2 reduces the creation of fat cells .
INSIG decreases triglycerides .
Excess INSIG2 appeared to suppress some of the actions of chemotherapeutic drugs .
INSIG-2 blocks lipid synthesis in a cholesterol-dependent fashion (by inhibiting the breakdown of SREBPs) .
INSIG2 increases SREBP. SREB proteins are indirectly required for cholesterol biosynthesis and fatty acid uptake and biosynthesis (by binding to SREBP cleavage-activating protein, SCAP). This prevents SCAP from escorting SREBPs to the Golgi) .
Exercise helps with this… People with an SNP that causes weight gain with a bad INSIG2 gene lost more weight with exercise .
13) Cannabinoids and Anandamide
In rats, anandamide (a natural cannabinoid produced by our body) injected directly into the nucleus accumbens enhances food intake as well .
Read my post on anandamide and the CB1 receptor.
14) Neuropeptide S (NPS)
NPS causes weight loss by reducing appetite.
Animal studies show that NPS suppresses anxiety and appetite, and induces wakefulness and hyperactivity, including hypersexuality, and plays a significant role in the extinction of conditioned fear .
It has also been shown to significantly enhance dopamine activity (in the mesolimbic pathway) .
15) PPAR gamma
PPAR gamma causes weight gain.
16) PPAR alpha
PPAR alpha causes weight loss.
17) PPAR Delta
PPAR delta causes weight loss.
PGC-1a causes weight loss.
SIRT1 promotes weight loss.
NAMPT causes weight loss through decreased appetite.
NAMPT/visfatin is the enzyme in the pathway to produce NAD+.
Furthermore, a gene polymorphism associated with increased circulating visfatin was also found to be related to appetite loss .
NAD+ causes weight loss by increasing metabolism.
SIRT3 promotes weight loss.
23) Adrenergic Receptors
Beta receptor activation causes weight loss, while alpha receptors cause weight gain.
Activation of beta receptors in the lateral hypothalamus produces satiation .
Beta2 and beta3 receptors break down fat cells .
Beta receptors are significantly increased after an acute stressor .
Norepinephrine and epinephrine activate these receptors (Beta receptors more than alpha receptors).
CTNNBL1 causes weight loss?
CTNNBL1 codes for Beta-catenin-like protein 1.
Beta-Catenin is involved in the Wnt/beta-catenin-signaling pathway which appears to contribute to inhibiting pro-fat gene expression 
This gene has some SNPs that are associated with obesity.
Bombesin causes weight loss.
Bombesin stimulates gastrin release from G cells.
Gastrin is a peptide hormone that stimulates secretion of stomach acid (HCl) by the parietal cells of the stomach and aids in the gut flow. Together with cholecystokinin (CCK), it is the second major source of feedback to stop eating .
Bombesin reduces food intake of normal and hypothalamically obese rats and lowers body weight when given chronically .
Bombesin can also cause anxiety .
Bombesin may help explain the thin/anxious phenotype.
Enterostatin causes weight loss.
Enterostatin is a peptide that reduces food intake- in particular, fat intake .
Low enterostatin output and/or responsiveness cause rats to become obese and prefer dietary fat .
Humans with obesity also exhibit a lower secretion of enterostatin after a test meal .
Its effects include a reduction of insulin secretion and an increase in the stress response, which causes the browning of fat tissue .
At the end level, it initiates a sensation of fullness of stomach which could be the reason for its role in the regulation of fat intake and reduction of body weight. For enterostatin to be utilized it needs the presence of CCKA receptors .
When rats have been injected with high doses of enterostatin into the brain the rats ate progressively less food as the dose was increased .
Beta-endorphins seem to cause weight loss.
Beta-endorphins seem to decrease food intake.
Mice engineered to lack beta-endorphin ate more and were obese .
Galanin promotes weight gain.
Galanin, a peptide found in the hypothalamus, has appetite-stimulating effects in a variety of species.
Galanin in the brain causes increased food intake in some animals, and the effect of galanin is associated with hypothalamic (ARC) activation .
29) Pancreatic Polypeptide (PP)
Pancreatic Polypeptide promotes weight loss.
This peptide decreases food intake .
PP leads to a reduction in food intake when given to rodents and/or humans .
PP also leads to an increase in energy expenditure and a reduction in body weight in rodents, and a reduction in appetite and food intake in both lean and obese humans .
The effects are mediated via the brainstem and hypothalamus (ARC) .
GIP causes weight gain.
Gastric inhibitory polypeptide promotes energy storage and weight gain.
Inhibiting this peptide combats obesity .
It was found that the absence of the GIP receptors correlates with resistance to obesity.
The GIP receptor is found in pancreatic tissue, where it causes the release of insulin .
It has been found that Type 2 diabetics have lower levels of GIP secretion after a meal when compared to non-diabetics .
GIP appears to be a major player in bone remodeling. When researchers knocked out the GIP receptor in mice, it resulted in negative changes to bones. Furthermore, the deficiency in GIP receptors has also been associated in mice with a dramatic decrease in bone quality and a subsequent increase in fracture risk .
31) Nerve Growth Factors
NGF suppresses food intake.
Nerve growth factor is reduced by stress, which is one reason why stress can cause weight gain. Lion’s Mane is a good way to increase NGF.
mTOR activation has tissue-specific effects. Activation in the hypothalamus reduces food intake, while in fat cells, it increases fat mass.
mTOR activation in the hypothalamus reduces food intake.
However, mTOR activation in fat cells increases fat mass.
PrRP causes weight loss.
This peptide contributes to satiation and a stress-induced decrease in appetite .
Acetylcholine causes mixed effects.
Acetylcholine helps weight loss through nicotinic receptors but can cause weight gain through muscarinic receptors.
The absence of M(3) muscarinic receptors (activated by acetylcholine) protect mice against some forms of obesity .
Mice without M3 receptors decrease food intake and weigh less. They have lower fat deposits and very low levels of leptin and insulin .
Paradoxically, MCH, an appetite-stimulating hormone, is increased by M3 activation. AgRP works in part through the M3 receptors .
Acetate causes weight loss.
Acetate results in appetite suppression .
Acetate activates acetyl-CoA carboxylase and causes other changes that favor appetite suppression .
Fermentation of fibers in the colon increases hypothalamic acetate .
Drinking Apple Cider Vinegar helps.
Lactate promotes weight gain.
Lactate increases appetite.
This may be one reason why exercise increases appetite.
FXR may promote weight loss.
Farnesoid X receptors are involved in sensing bile acids.
Intestinal FXR activation promotes the browning of fat tissue and reduces obesity and insulin resistance .
Bile activates intestinal FXR receptors, which might lead to weight loss.
SREB1c may cause weight loss?
Sterol regulatory element binding proteins (SREBPs) are transcription factors that are involved in fat cell creation.
Insulin is a driver of SREBP’s .
In states of insulin resistance or deficiency, there is a decrease in SREBP1c .
Insulin-resistant states, such as obesity and type 2 diabetes, are characterized by decreased production of SREBP1c. The decreased expression of this molecule in obese and diabetic human subjects could play an important role in the induction and/or maintenance of the insulin resistance seen in these disorders .
SREBP-1c was associated with fatty acid synthase and acetyl-CoA carboxylase alpha gene expression in the fat tissue of obese humans .
TPH1 causes weight gain.
The majority of serotonin in the body is produced by tryptophan hydroxylase (Tph1).
When this enzyme is inhibited, mice fed a high-fat diet were protected from obesity, fatty liver disease and pre-diabetes due to an enhanced ability of the brown fat to burn more calories .
40-41) FGF21, FGF19
FGF-21 increases energy expenditure and FGF19 is an appetite suppressant.
Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin-resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes .
FGF21 has been a key target for developing weight-loss drugs because the protein increases energy expenditure, causing the body to burn calories .
FGF21 acts directly on the brain, activating another hormone called corticotropin-releasing hormone. CRH then stimulates the nervous system, activating brown fate, which generates body heat by burning fat .
Brown fat is often considered the “good” fat that actually burns energy by generating heat—called thermogenesis—to protect from the cold. Once brown fat receives a “weight loss” signal, the tissue burns fat .
Butyrate helps increase FGF-21.
42) Glycerol 3 Phosphate Dehydrogenase (GPDH)
GPDH causes weight gain.
Enhanced GPDH activity, particularly GPD2, leads to an increase in glycerol production. Since glycerol is the backbone in triglycerides, its abundance can easily lead to an increase in triglyceride accumulation at a cellular level. As a result, there is a tendency to form fat tissue leading to an accumulation of fat that favors obesity .
The mitochondrial form of GPDH is thought to be inhibited by metformin, a first line drug for type 2 diabetes .
DSIP causes weight gain.
Delta sleep-inducing peptide, abbreviated DSIP, is a neuropeptide that when infused into the brain, induces delta EEG activity and reduced activities .
Studies have demonstrated a direct link between GILZ (similar to DSIP) and fat tissue creation, obesity and metabolic syndrome .
Amylin causes weight loss.
Amylin slows stomach emptying and promotes satiety.
Amylin decreases hunger by inhibiting dopamine release in the hypothalamus .
Pramlintide, an amylin analog, improves blood glucose and also reduces appetite and weight .
Amylin is co-secreted with insulin.
45-50) Micro RNA (miRNA)
miR-143, miR-34a, miR-335, miR-519d, and miR-150 causes weight gain. miR-659 causes weight loss.
In fat tissue of obese mice, there were increased levels of miR-143 .
miR-335 was found to be increased in obesity models. During fat cell creation miR-335 is strongly induced, suggesting miR-335 may play a role in increasing the mature fat cell population .
In human fat tissue, overproduction of miR-519d was reported to be associated with severe obesity . During fat cell creation, miR-519d is stimulated in a dose-dependent manner, which suggests miR-519d may be a factor in the enlargement of fat cells and increased fat tissue mass in human obesity .
In fat tissue from obese subjects, miR-150 was reported to be increased and miR-659 was reported to be decreased .
NOR1 causes weight loss.
Hypothalamic NOR1 was remarkably decreased in mildly obese beta-endorphin-deficient mice and obese mice with the leptin receptor mutation, compared with age-matched wild-type mice.
The injection of NOR1 into the brain significantly suppressed food intake and body weight in mice.
On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice.
These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance .
52) Beta 2-Microglobulin
Beta 2-microglobulin causes weight loss.
Beta 2-microglobulin may decrease eating, and this effect may participate in the anorexia frequently accompanying disease .
Resistin is a hormone secreted from fat tissue, whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes.
Many scientists think it causes weight gain .
54) Nucleobindin2 (NUCB2)/Nesfatin-1
Nucleobindin2 causes weight loss.
Nucleobindin2 (NUCB2) suppresses appetite.
Nucleobindin2 produces Nesfatin-1 .
Nesfatin-1 inhibits appetite, acting in a leptin-independent manner .
Inflammation increases 5-HT2C receptors, which is part of the mechanism for suppression of appetite.
It may also increase blood pressure .
55-58) EGF, bFGF, PDGF, and PF4
Injection to the brain of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and platelet factor 4 (PF4) suppressed food intake in rats. Infusion of platelet-derived growth factor (PDGF) suppressed only 2 h food intake .
TAAR1 activation causes weight gain.
The trace amine-associated receptor 1 (TAAR1) is found in the rat hypothalamus. Rodent studies show that T1AM significantly increases food intake in rats .
Thyroid hormone derivatives activate TAAR1.
Tyramine, which is a derivative of the amino acid tyrosine, also activates this receptor.
Foods containing considerable amounts of tyramine include meats that are potentially spoiled or pickled, aged, smoked, fermented, or marinated (some fish, poultry, and beef); most pork (except cured ham). Other foods containing considerable amounts of tyramine are chocolate; alcoholic beverages; and fermented foods, such as most cheeses (except ricotta, cottage, cream and Neufchâtel cheeses), sour cream, yogurt, shrimp paste, soy sauce, soybean condiments, teriyaki sauce, tempeh, miso soup, sauerkraut, kimchi, broad (fava) beans, green bean pods, Italian flat (Romano) beans, snow peas, edamame, avocados, bananas, pineapple, eggplants, figs, red plums, raspberries, peanuts, Brazil nuts, coconuts, processed meat, yeast, an array of cacti and the holiday plant mistletoe.
Histone deacetylase (HDAC) inhibitors cause weight loss .
61) Mitogen-Activated Protein Kinase (MAPK)
MAPK causes weight gain.
The MAPK pathway increases fat cell production .
Obese Zucker rats exhibit MAKP activity .
MAPK phosphatase-1 (MKP-1) decreases the activity of MAPKs .
Mice lacking MKP-1 expression are resistant to diet-induced obesity .
In both dietary and genetically obese mice, fat tissues have less p38MAPK activity compared with the same tissues from lean mice .
The MAP2K5-linked SNP was associated with BMI and obesity in two cohorts of Swedish and Greek children .
62) S-Adenosyl methionine synthetase 1
S-Adenosyl methionine synthetase 1 causes weight loss.
S-Adenosyl methionine synthetase 1 limits fat storage in C. elegans .
Notch causes weight gain.
Inhibition of Notch signaling promotes browning of white fat tissue and ameliorates obesity .
FOXO1 causes weight gain?
Forkhead box-containing protein of the O subfamily 1 (FoxO1) in the hypothalamus increases food intake. It’s inactivated by insulin .
LXR has mixed effects on weight.
It’s not clear exactly what the effect of Liver X Receptors (LXR) on weight is, but it has an effect depending on a variety of environments and factors.
Activation of LXR seems to increase fat oxidation in white fat cells, it suppresses energy dissipation in brown fat cells .
See my post on Liver X Receptors (LXR).
IRX3 causes weight loss?
The IRX3 gene is increased together with weight loss in human fat cells .
67-70) PFKP, KCNJ11, PTER and SEC16B
Genetic variations in PFKP, KCNJ11, PTER, and SEC16B were associated with obesity. They may cause obesity by causing an increased risk of being born small .
I have not worked out the mechanisms by which these are associated with obesity.
Phosphofructokinase (PFK) is an enzyme in the glycolysis pathway and seems to be involved in obesity.
People with variations in the PFKP (PFK-Platelets) gene have increased obesity .
Mice deficient in phosphofructokinase in the muscle have greatly decreased fat stores .
71) 5HT2C Receptors
5HT2C activation causes weight loss.
Besides inhibiting appetite, these receptors cause lower insulin from the pancreas , which is a common feature in the chronic fatigue people I deal with.
Antipsychotics often block the 5HT2c receptor, which is one mechanism by which they cause weight gain.
72) Histamine Receptors
CEBPB causes weight gain and the inflammation that results from obesity.
CEBPB is a transcription factor that activates PPAR gamma .
Mice without CEBPB are protected from high fat diet-induced inflammation.
These mice have an increased ability to turn white fat into brown fat .
Mice without PARP-5 had increased energy expenditure, fatty acid and glucose utilization, and reduced fat .
REV-ERB agonists reduce body weight in mice that were obese due to diet .
76) Nitric Oxide
Nitric Oxide (NO), as a signaling molecule, stimulates glucose uptake as well as glucose and fatty acid oxidation in muscle, heart, liver and fat tissue; inhibits the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhances fat breakdown in fat cells .
NO stimulates AMPK, resulting in a decreased expression of genes related to fat and glucose creation (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c, and phosphoenolpyruvate carboxykinase) .
NO increases the activation (phosphorylation) of hormone-sensitive lipase and perilipins, which results in the breakdown of fat .
NO activates expression of PGC-1a, thereby enhancing mitochondrial creation and function .
NO increases blood flow to insulin-sensitive tissues, promoting uptake of glucose and fat, which removes it from circulation .