Unveiling the Genetic Code of Obesity: Scientific Insights from PPAR to UCP for Weight Loss

Peroxisome proliferator-activated receptor (PPAR) family

PPARs are a class of nuclear receptors that regulate lipid metabolism, translating nutrient signals into gene expression processes. There are four subtypes of PPARs: α, β, γ, and δ. PPAR-α primarily mediates lipid oxidation, such as β-oxidation of fatty acids, while PPAR-γ mediates adipocyte differentiation and fat storage. PPARs have many ligands, including fatty acids, thiazolidinediones, and prostaglandins. Activated PPARs must bind to the retinoic acid X receptor (RXR) to form a heterodimer before binding to target genes, thereby regulating their expression. Most PPAR target genes are related to the regulation of lipid metabolism, including various genes involved in intracellular and extracellular lipid metabolism, such as peroxisome genes, apoA-I genes, apoA-II genes, apoC-III genes, and acyl-CoA synthesis genes. PPARs regulate these lipid metabolism genes through several mechanisms:

① Inhibition of apoc-III apolipoprotein synthesis and enhancement of CPV enzyme synthesis: After activation by their corresponding ligands, PPARs can inhibit the expression of the apoc-III gene while activating the expression of the VPC gene. This reduces apoc-III synthesis while significantly enhancing VPC synthesis and activity. This promotes lipoprotein breakdown and clearance by accelerating lipolysis and increasing the rate of receptor-mediated lipoprotein clearance, thus reducing the number of triglyceride-rich lipoprotein particles in plasma and forming a less atherogenic lipoprotein profile.

② Stimulation of cellular fatty acid uptake and conversion into acyl-CoA derivatives.

③ Induction of fatty acid β-oxidation pathway.

④ Reduction of fatty acid, triglyceride, and lipoproteins such as apoB and VLDL.

(V) Uncoupling Proteins (UCPs)

Brown adipose tissue plays a crucial role in non-shivering thermogenesis and energy balance. UCPs are key factors determining the function of brown adipose tissue. There are two types of UCPs: UCP1 and UCP2. UCP1 is mainly distributed in the inner mitochondrial membrane of brown adipose tissue, while UCP2 is distributed in human skeletal muscle, brown adipose tissue, white adipose tissue, spleen, and lymph nodes. UCP2 may be related to altering the expression and function of "thrifty genes."

The factors regulating UCPs are very complex, with both individual and synergistic effects, and many mechanisms remain unclear. Currently, several factors are believed to regulate UCP thermogenesis:

① Norepinephrine.
② Heat shock proteins.
③ Thyroid hormones: Thyroid hormones can directly stimulate UCP expression after binding to their receptors.
④ Retinoic acid: The UCP gene has a specific retinoic acid response region; retinoic acid can stimulate UCP gene expression. Retinoic acid can also inhibit the normal differentiation of white adipose tissue, causing it to differentiate into brown adipose tissue. ⑤ Insulin: Insulin regulates the thermogenesis of UCPs by modulating mitochondrial UCP concentration and quantity.

Endorphins

The endorphin opioid system is closely related to obesity. Obese individuals have significantly elevated levels of β-endorphin in their blood, which are positively correlated with body weight.

The effect of opioids on feeding is a biological evolutionary legacy. In invertebrates, the opioid system participates in regulating basic behaviors and physiological processes, including feeding. In mammals, endogenous opioid antagonists also participate in controlling feeding behavior.

Besides affecting feeding, endorphins also regulate metabolism through hormones such as thyroid hormones, growth hormone, insulin, and gastrointestinal hormones, leading to obesity. (VII) Epidemiological Survey of Genetic Factors

Body mass index (BMI), localized fat distribution, basal metabolic rate, energy intake and expenditure, physical activity habits, and nutrient utilization are all influenced by genetic factors. These genetic factors result from the interaction of multiple genes.

1. BMI

A study surveyed 75,000 individuals, all within first and second-degree family units. The correlation coefficients for BMI were 0.12 between spouses, 0.20 between parents and children, between children of different sexes and between dizygotic twins, 0.26 between children of the same sex, and 0.58 between monozygotic twins. The correlation coefficient between second-degree relatives was almost zero.

2. Localized Fat Distribution

Human fat distribution exhibits familial characteristics. The heritability of subscapular skinfold thickness is 77%, while the heritability of subscapular and triceps skinfold thickness is 29%, with a ratio of 17%. Therefore, genetic factors are considered to play a significant role in human fat distribution.

3. Calorie Intake

Calorie and nutrient intake show clear familial characteristics.

4. Energy Expenditure

After adjusting for age, time, and BMI, the heritability of basal metabolic rate is 80% in monozygotic twins and 40% in dizygotic twins.

One study reported that the correlation coefficient of the thermic effect of food between parents and offspring was 0.03, 0.35 between dizygotic twins, and 0.52 between monozygotic twins, thus suggesting that the heritability of the thermic effect of food is 40%–60%. Heredity influences physical labor and sports activities to some extent.