Introduction
Genetic risk factors for developing obesity
risks of obesity
pharmacologic options
surgical options
- gastric laparoscopic banding (lap banding)

obesity and weight management

Introduction

obesity is a complex major increasing global health issue
there are 3 types of fat cells:
- white fat cells found in white adipose tissue (WAT) which serve mainly as energy reserves
  - obesity is a measure of the excessive fat stores within these cells which contribute to the metabolic syndrome
- brite / beige fat cells which can function as a combination of white and brown fat cells
  - these are found mainly in subcutaneous white adipose tissue rather than in visceral white adipose tissue
  - subcutaneous white adipose tissue white fat cells can be converted to beige fat cells by either:
    - exposure to cold
    - various dietary modifications
    - reduction of function of the protein KLF-15 within the white fat cell ¹⁾
      - this protein is one of the Kruppel-like factors (KLFs) which are zinc finger motifs containing transcription factors that regulate development and systemic metabolism and dysregulation of KLFs results in diseases, including obesity and the development of diabetes. Klf15 expression is higher in WAT compared with BAT and is suppressed by β-adrenergic signaling. ²⁾
      - this protein controls the abundance of the beta-1 adrenergic receptor (Adrb1), which helps maintain energy balance
        
        overexpression of Adrb1 in white adipocytes is sufficient to generate constitutive activity and mimics the effect of systemic infusion of agonists, even in the absence of additional agonists and overexpression of Adrb1 in subcutaneous white adipose tissue (iWAT) is sufficient to induce Ucp1 expression and beiging of this white fat depot ³⁾
        
        deletion of Klf15 disrupts maintenance of white adipocyte properties and induces Adrb1 expression
- brown fat cells found in brown adipose tissue (BAT) and which are designed to burn fat to maintain body temperature in infants
  - humans appear to have few BAT depots at birth and but which largely disappear by 1st year of life and these largely disappear by 1st year of life and hence much effort has been put in trying to increase these stores as they are felt to be beneficial whereas WAT stores are detrimental
  - brown fat responds to β-adrenergic signaling with the induction of thermogenesis and brown fat has ~75% lower expression of KLF-15 than does WAT
  - it appears that caloric restriction lowers body cysteine levels and low body levels of cysteine drives high levels of weight loss and increased fat burning and conversion of fat cells to brown fat cells. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1.⁴⁾
    - cysteine is in most food sources, especially meats, eggs, dairy, soy, lentils, nuts and seeds and is critical for protein production, glutathione production and other metabolic processes - so eradicating it from diet is not easy and would be dangerous

Genetic risk factors for developing obesity

childhood obesity

rs7132908 locus at chr12q13 appears to have a strong association ⁵⁾
genetic causes of early menarche

syndromic

Prader-Willi Syndrome: Caused by the loss of function of genes on chromosome 15
Bardet-Biedl Syndrome: A genetic disorder affecting multiple body systems with obesity as a major feature

polygenic factors

FTO (fat mass and obesity-associated gene)
- Variants in this gene are among the most common genetic factors associated with obesity and can influence energy intake and metabolism
BDNF, SH2B1, and SIM1:
- These genes are involved in brain pathways that regulate energy balance
ADCY3 gene plays a significant role in obesity through its involvement in energy homeostasis and metabolic processes. ADCY3 encodes adenylate cyclase 3, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), a crucial second messenger in cellular signaling pathways.
INSIG2 (Insulin Induced Gene 2)
- may have a role.
TRPC5 gene
- Pomc neurons in the arcuate nucleus of the hypothalamus help regulate body weight by reducing food intake, and about 90% of these cells express Trpc5. Impaired TRPC5 results in over-eating.
- there are also high levels of Trpc5 expression in oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVH) in mice. This specific group of neurons in the brain is known to regulate energy balance in the body and the response to stress, emotion and social behaviors including mother-infant bonding and deficiency may play a role in post-natal depression.
- it is thought overeating and obesity of TRPC5 deficiency is mediated by impaired activation of Pomc neurons, this disorder may be treatable with an MC4R agonist drug licensed for the treatment of genetic obesity syndromes ⁶⁾

rare monogenic factors

LEP (leptin gene)
LEPR (leptin receptor gene)
POMC (pro-opiomelanocortin gene)
MC4R (melanocortin-4 receptor gene)

risks of obesity

cardiovascular disease:
- in white Causasians, cardiovascular risk increases by 13% for every 5.2 kg/m2 increase in women and 4.3 kg/m2 in men above an optimum level of 22-23 kg/m2 and, compared to women and men with waist circumferences of 74 and 83 cm respectively, the CVD risk increased by 16% in women and 10% in men for every 12.6 cm and 11.4 cm increase in waist circumference for women and men respectively.⁷⁾
cancer
- metabolic syndrome (3 or more of TG > 1.7, HDL < 1.0 males or 1.3 females, fasting glucose > 6.1 and non-fasting > 7.8, BP > 130/85, BMI > 25) appears to increase risk of pancreatic cancer ⁸⁾
diabetes
insulin resistance
high sugar or fructose diet
- small intakes of sucrose or fructose are converted to glucose by enterocytes in the small bowel which is then metabolised by the whole body as needed
- excessive intakes of sucrose or fructose results in fructose being absorbed into the circulation and then it must be metabolised into fat primarily within the liver
osteoarthritis
deep venous thrombosis (DVT)
mental health issues
possibly impaired immunity and increased osteoporosis
- increased bone marrow fat in mice appears to drive immunosuppression and osteoclast activity via altering the molecular profile of adipocytes, increasing the production of signaling molecules such as MCP-1, which recruits and reshapes myeloid immune cells, markedly increasing PD-L1-expressing myeloid cells within the bone marrow which suppress T-cell activity, and via PD-1 receptors on osteoclast precursors, promoting their differentiation into mature osteoclasts.⁹⁾
medical iatrogenic risks
- vascular access issues
- pressure sores
- complexity of medical and surgical procedures increases
- ultrasound not as readily diagnostic

pharmacologic options

glp-1 analogs

see glucagon-like peptide-1 (GLP-1) peptide analogs (eg. Ozempic)

lipase inhibitors

orlistat

5-HT2C selective agonists

lorcaserin is a selective 5-HT2C agonist with 15x more activity than on 5-HT2A receptors, and 100x more activity than on 5-HT2B receptors
- under trial for obesity management in 2010¹⁰⁾ - appears to reduce weight by ~6kg in 1 year compared with 2kg for a placebo with almost 50% of patients losing at least 5% body weight compared with only 20% of those on placebo.

GIT biome supplements

Akkermansia muciniphila appears to improve pre-diabetes and reduce weight in an initial study ¹¹⁾

other drugs which have been tried but adverse effects generally outweigh benefits

non-selective serotonin agonists

fenfluramine and dexfenfluramine was approved for Mx of obesity in the USA by FDA in 1973 and 1996 respectively
both were withdrawn in 1997 after they were found to cause serotonin associated cardiac valvulopathy which is thought to be due to agonism of 5-HT2B receptors, and is similar to that seen in carcinoid heart disease and ergot-alkaloid induced heart disease.

cannabinoid-receptor antagonists

rimonabant was withdrawn from the market in Europe because of an increased risk of depression, anxiety and suicidal ideation.

reuptake inhibitors

the serotonin and noradrenaline reuptake inhibitor, sibutramine, was removed from the European market after a 100,000 patient, 6-year SCOUT study showed an increased risk of serious nonfatal cardiovascular events such as stroke or heart attack.

potential future drugs

SCoR2 inhibitors
- SCoR2 is needed to make fat and removes nitric oxide from proteins controlling fat build up which in turn results in turning on fat synthesis¹²⁾
- in the liver, nitric oxide inhibits the proteins that make fat and cholesterol. In fat tissue, nitric oxide inhibits the genetic program that makes the enzymes that create fat.
- SCoR2 mRNA or protein abundance correlated with obesity, adipocyte surface area, or steatotic liver disease in patients