Treat your diet as a bank account, Don't let disease disguise as EMI and vacant your wealth filled account all of a
sudden. Be calculative and put a check on investments like healthy diet, exercise and many more to ensure wealth,
As health is the real wealth...!
Today, obesity and its associated comorbidities has become the number one public health issue. Since the dawn
of history, chronic food shortage has been a great scourge of mankind. But surplus availability of food, genetic
predisposition and sedentary lifestyle has switched the circumstances. Although obesity boutade is a few decade
old, adversities ushered by it are limitless. In fact after the second world war, change in dietary habits, easy access
to facilities and reduced physical activity has accounted for an increased prevalence of obesity. Its epidemic has
spread widely sparring neither the affluent societies, nor the developed and developing countries. Adiposity have
altered energy regulation and balance which has made us witness unfavorable consequences. Obesity has been
recognized as a public health problem worldwide that affects multiple organ systems.
Obesity and Diseases The Obnoxious Connection
Obesity, according to World Health Organization, is a condition wherein BMI is equal to or higher than 30 kg/m .
Evidences of link between obesity and associated maladies have been successfully garnered. It has been found
to be associated with several costly medical problems, including type 2 diabetes, Hypertension, coronary artery
disease as well as different forms of cancer. Both cancer and obesity are the two major outbreaks of the century.
Plausible mechanisms are present that explain the complex relationship between the two up to certain magnitude.
The Obesity Paradox in Cancer
Obesity is recognized as the most prominent risk factor of cancer; a headline concern among the ethnicities and
nations. Association between obesity, cancer and elevated mortality has been confirmed by astonishing number
of studies. Apocalyptic proportions has been touched up till now with huge sums of affected adults, and also
children. Lack of physical exercise, a high-fat diet, drinking alcohol, Smoking and obesity-induced High cholesterol
levels are top modifiable risk factors which may trigger its occurrence. Possible factors like genetic variations,
biological pathways and environmental factors influences has been related to the increasing body mass index
(BMI) and cancer risks.
The Genetic Link
Obesity has been connected with the etiology of several cancers, basis of which are genetic predisposition,
mutations in various pathways and impaired biological mechanisms. Coexistence of multiple obese individuals
in a family describes a strong evidence of inheritance. Studies on genetic components of family history revealed
risk of two to three fold for moderate obesity and up to eight times for severe obesity. Search for obesity susceptibility
variants carried out using candidate gene association studies or linkage analysis demonstrate clear inheritance
patterns. Studies based on inheritance pattern describe that the propensity to become obese is heritable and may
predispose them to cancers such as endometrial, colorectal, breast and many more. Genome-wide scans, linkage
studies and candidate gene research highlighted that more than 400 chromosomal regions that may harbor variants
and make one prone to increased body size. Genes connected with obesity like SDCCAG8, serologically known as
colon cancer antigen-8, may play critical role in its inheritance. Multiple systemic and local pathways mediate the
pleiotropic effects of obesity, which lead to cancer progression. A number of investigators are focussing on gene
encoding for insulin signaling, adipocyte metabolism and differentiation, and regulation of energy expenditure pathways
in relation to colorectal neoplasia.
With the improvement in technology and accelerated pace in genome-wide association studies, obesity genetics
and its relationship with cancer genes are widely studied especially for breast and colorectal cancer. When the obesity
gene map is superimposed with cancer gene maps, connections with chromosomes 11p and 16 for breast cancer and
189 for colorectal cancer has been discovered. Additionally, in animal models of cancer, it is seen that by maintaining
appetite, lean body mass and basal energy expenditure MC4R (a key receptor involved in appetite control and energy
homeostasis) antagonise impaired cachexia.
From Obesity to Cancer: Unraveling Mechanism
- Diet
Positive energy balance, alteration in calorie intake or quality of diet significantly influence the risk of cancer
development and its progression. However, a balanced and diversified diet (along with avoidance of tobacco
use and reduction in alcohol intake) should be considered for prevention of cancer.
- Physical Inactivity
It has been estimated that 50% of cancers are preventable. Maintaining an optimal level of energy balance-calorie
expenditure relative to calorie intake is connected with primary prevention of cancer, survival after diagnosis and
recurrence of primary cancer. Participation in physical activity has emerged as a potent rehabilitative modality for
cancer survivors in the past years.
- Insulin Resistance
Chronic hyperinsulinemia is evident in obesity and has been found to cause colorectal, pancreatic, endometrial
and breast cancer. Both insulin receptors and endogenous hormone metabolism have a role in carcinogenesis
mechanism of insulin. insulin growth factor 1 (IGF1) promote cell proliferation and inhibit cell apoptosis.
Hyperinsulinemia also affects the production of sex hormones (androgen and estrogen) which may be allied with
cancerous growth.
- Sex Hormones
Evidences are continuously mounting to establish possible role of sex hormone in triggering obesity and cancer.
Estrogen bind to estrogen receptors and activate intracellular signaling pathways which in turn initiate the tumor
progression by stimulating cell division. Additionally, overproduction of aromatase by adipose tissue in obese individuals
increases the level of unbound estradiol which can damage the DNA. The interaction of estrogen with insulin like
growth factors also promotes tumor growth and inhibit apoptosis.
- Adipose Tissues
Fat tissues secrete adipokines among which leptin has been largely studied as a potential mediator of obesity induced
cancer. It activates the phosphoinositide 3-kinase (PI3K), mitogen activated
protein kinase (MAPK) and STAT3 which in turn induces cancer progression. Adiposity have been associated with
high levels of proinflammatory cytokines including prostaglandin E2, TNF-a, IL-2, IL-8, IL-10 and monocyte chemoattractant
protein (MCP)-1. While activation of nuclear factor-kappaB (NF-kappaB) complex may stimulate the cancer development
through inflammation.
Obesity and Hypoxia
In obesity, adipose tissue hypoxia may cause insulin resistance, chronic inflammation, increase in leptin, adipocyte
death and mitochondrial dysfunction. Thus, can contribute to cancer risk in obese individuals. Hypoxia regulates
hypoxia-inducible factor 1 alpha (HIF-1a) which increases vascularization in tumors. Studies also show that melanoma
growth favors a hypoxic environment.
Oxidative Stress
Gago-Dominguez and colleagues suggested that obesity induces oxidative stress and increases damage to DNA due
to which risks of cancer may arise.' UV-induced oxidative stress promotes tumor growth by activation of NF-kappaB
pathways.
Different Cancers Caused Due to Obesity
Adequate evidences support occurrence of several cancers in obese people, including colon, breast, endometrial, kidney
and esophageal. The percentages attributed to obesity derived cancers are 39% for endometrial, 37% for esophageal,
25% for kidney, 11% for colon and 9% for postmenopausal breast cancer. A meta-analysis done by Renehan and colleagues
suggested that obese men are at higher risk of esophageal adenocarcinoma, cancer of thyroid hormones, kidney and colon multiple
myeloma. On the contrary, in obese women endometrial, gallbladder, kidney, esophagus and post menopausal breast
cancer are prevalent. Therefore, some evidences suggest that obesity and cancer is sex specific; few of which are
described as under.
- Endometrial Cancer
Hormone based interaction stimulates endometrial epithelial cells due to increased levels of estrogen are observed.
When progesterone does not suppress the levels of estrogens, it leads to cancer. Obese women have high levels of
estrogen and estradiol due to aromatization of androstenedione in the adipose tissue and lower levels of sex hormone binding globulin. Thus, posing a higher threat of such cancer in women.
- Prostate Cancer
Analysis suggests that there is a positive connection between increased BMI, weight gain and prostate cancer.
Numerous hormonal changes in the levels of testosterone, estrogen, insulin, insulin-like growth factor (IGF-1,
and leptin) have been implicated for development and progression of prostate cancer. Severely obese men are 34%
more susceptible to prostate cancer as compared to men with normal weight.
- Pancreatic Cancer
Cachexia is a characteristic feature of pancreatic cancer. Studies assessed that measures of adiposity that includes
pooled and meta-analyses results support a positive associations with waist to hip ratio. Clarification on modifiable
risk factors for pancreatic cancer such as BMI may provide new insights about pancreatogenesis. Efforts to reduce
incidences have notably improved prognosis in high risk populations.
- Breast Cancer
Presence of epithelial cells near adipose tissues is the initiating factor leading to tumorogenesis in breast. Effects of
obesity in premenopausal and postmenopausal women differ on the basis of estrogen receptors (ER). In premenopausal
women lower risk of ER-positive breast cancer and a higher risk of triplenegative (ER, progesterone receptor and human
epidermal growth factor receptor 2) breast cancers (TNBC) has been found. Stronger associations between BMI and breast
cancer risk have been explored in Asia Pacific area.
- Colorectal Cancer
Insulin resistance looms largely in theoretical framework that connects obesity and colon cancer, and hyperinsulinaemia
has been credited for pathogenesis of colon cancer. Obese men of all ages and premenopausal obese women are at
increased risk for colon cancer. Visceral abdominal fat is an established presumptive metabolic risk factor for colon cancer.
Renal Cell Carcinoma (RCC)
Several potential risk factor identified includes obesity, tobacco smoking, hypertension and a familial history of kidney
cancer and may account for etiology of RCC. However, several worldwide studies demonstrate a strong influence of
BMI and weight on renal carcinogenesis.
Lifestyle and Cancer Risk
Despite the presence of overwhelming evidences, very little is known about the underlying mechanisms leading to
cancer incidence and its progression. The knowledge gap is a big obstacle towards the implementation of lifestyle
changes like diet modification and undertaking energy expenditure physical activities. Current lifestyle has driven
the obesity prevalence to epidemic proportions. Especially associated cancer adds on to the morbidity and mortality
rates. Protecting cellular signaling and protective pathways from disruption can be accomplished by preventing
carcinogenic exposures from outside the body through any source. As, obese individuals with particular genetic
predisposition may become more susceptible to the ill effects of environmental exposures than others. Scientific
communities and administrators are uncertain, what to recommend and what not thereby creating a confusing
circumstance for common man as to whom should they believe. Thus, leaving the floor flooded with pseudoscientific
recommendations that are hard to believe and eradicate.
Rising rates of obesity linked cancer across the globe are worrisome. Research on mechanisms underlying the
obesity-cancer relation are still in its early stages. The increasing prevalence of obesity in many parts of the
world has emphasized the importance of learning more about its relationship and mechanisms involved in their
interaction. Transparent understanding of carcinogenesis in obesity-related cancers as well as potential treatments
and preventive agents may safeguard many lives in future.
