Etiology of Obesity & PCO

Inability to lose weight inspite of attending Gym is not uncommon and musty related to genetics. People from the Indian subcontinent   are highly prone   to central obesity    and diabetes   either within   those countries   of the subcontinent or after migration to the United  Kingdom . This is genetic like “The thrifty phenotype hypothesis in obesity “though recent   evidence   suggests that not all groups of people are equally vulnerable.  “Have nots “ à now have “plenty”   and  it is her mother got this imprinted while the so called accused teenagers(your patient at OPD) was in her mother’s womb. Barkers hypothesis, Genetics of adult onset of foetal Diseases. There is  at the moment no answer to us for such adolescents, What message we can offer to her who is already in pipeline of lifestyle changes (Gym, Carbo restricted diet).. According to the general   thrust of the thrifty phenotype hypothesis, the most   important measure   for determining risk of metabolic syndrome   should be the speed   of transition from a “life of thrift “ to  a “ life of plenty”  .

                                                                                                                                                                                                                                                                                                    Why Indian people of India fail to gain weight??  :- People from the Indian subcontinent   are highly prone   to central obesity    and diabetes   either within   those countries   of the subcontinent  or after migration to the United  Kingdom . This is genetic like “The thrifty phenotype hypothesis in obesity “ though  recent   evidence   suggests  that not all groups of people are equally  vulnerable. According to the general   thrust of the thrifty phenotype hypothesis, the most   important measure   for determining risk of metabolic syndrome   should be the speed   of transition from a “ life of thrift “ to  a “ life of plenty”  .

Can we explain all obese PCO on this theory- ??? However   this part of the hypothesis does not always    hold true. It is not true for example  in the case  of Tibetans   who have   migrated to India. Coming from  a life of thrift environment in Tibet to a more life of plenty environment in India, the  Tibetans in India would   according to the thrifty  phenotype hypothesis be expected to be more  prone to diabetes than    peninsular   Indians.

What about Tibetans??  That is not the case however   Tibetans who have migrated to India are less prone to diabetes that peninsular Indians. Similarly Japanese who    migrate to Hawaii and Los  Angeles might be   expected to be more   prone to diabetes than people  who have lived in Hawaii or   Los Angeles for generations. Data show   otherwise however Japanese  migrants  to those  two places are less prone to obesity   and diabetes than the established populations. These   observations have led  to the hypothesis  that another key  factor in determining risk   is climate

. CAN  it be  explained by gene   environment   interactions ?  It is   now widely accepted that genetic and epigenetic pathways   mediate much of the relationship between the environment   and the  developmental  origins of health  and disease   paradigm. Sequence variation      within the genetic modification of the genome can   influence an individual’s risk  of health and disease   . Both    mechanisms   likely contribute   to the variation   seen in an individual’s response   to the environment though  their relative   contributions   and the extent of  interactions between  the pathways   remain  to be determined.

Where is your birth place ??  This is not related to NCA???  But to obesity.

Believe me obesity is related to your ancestors living place!!!!   Where your ancestors lived??? Risk may be lower for  groups whose ancestors lived   in cold hares   climates. In an environment in which agriculture and hunting is not   possible    for much of the year reliance on limited quantities of   stored   food may be expected to result in insulin resistance. The principles that underpin the thrifty phenotype  hypothesis   would suggest  that such   descendents   would be more at risk of diabetes, rather than  less. This leads to the possibility  that different groups of people may have   different  genetic  predispositions   to obesity  and diabetes.

Fat, Fat,  Fat –fat is discussed everywhere-In all conferences /CME/ Seminars   everywhere : But who will discuss and talk about free  Fatty acids??? Effects of gender and obesity on fatty acid and triglyceride metabolism in the post absorptive state

  Ans & explanation on Free fatty acids :-Circulating FFAs which    are mainly derived from the breakdown of endogenous triglyceride stored  in adipose tissue   are  an important  sourced of fuel. FFA   release from adipose tissue is well regulated by the coordinated action of many  endocrine paracrine and   other  factors, allowing   appropriate    availability of FFA  to meet   the  energy   requirements of tissues., which   is thought to be  responsible  for many of the metabolic  abnormalities  associated  with obesity including   hypertriglyceridaemia and insulin  resistance.

In the   post absorptive state  the rate  of FFA   release into the circulation at the whole body level  is not  different   between  men and women    matched for body  mass index  level  is not different between men and women matched  for body mass index whether lean or obese . However this comparison although often made  does not take into account differences in body size  between  men and women . In fact   FFA   release relative  to lean mass  an  index of FFA   released  into plasma in relationship to the  tissues that consume FFA  for use as a fuel  is greater in women than men whereas FFA  release    relative to the size  of adipose   tissue  - an  index  of FFA released into plasma with respect to the recently found that the differences in FFA release   between  men and women  present   in lean overweight   and obese individuals and  are  largely  a result of differences  in  Ra increased  linearly with   increasing   fat mass and there were    no differences between  men and women in the relationship between   fat mass and total FFA Ra. Consequently  FFA  Ra in relationship to fat free mass is   grater in obese   than lean  subjects    and greater  in women   than in men . Very  similar observations have been made   for FFA Ra in relation   to resulting energy expenditure   most likely because of the close relationship between resulting energy  expenditure and fat free mass.  Despite  the considerable lipolytic heterogeneity between   different  adipose   tissue regions  FFA release   from upper  body  patterns of fat storage in the body between  genders, there   are no  major differences  upper body   nonsplanchnic  subcutaneous adipose tissue beds  to whole  body FFA   Ra. Increased   release of FFA in obese compared     with lean subjects   is predominantly  because   of increased FFA release  rates from splanchnic and lower body adipose tissues but  not from   upper body   non splanchnic adipose tissue.

In summary FFA release into plasma  appears  to be tightly associated with energy requirements of lean tissues however   for any  given amount of fat  free tissues or energy  expenditure    plasma FFA  availability is  greater in women than in men and in obese than   lean subjects   because   women and   obese subjects  have more  body fat than men and lean subjects   respectively.

The   majority  of plasma   triglyceride in the fasting  state  circulates  in the core of VLDLs, which    are produced   and  secreted  by the liver  thereby providing   energy  dense  substrates  to  peripheral tissue  while  at the same time buffering excess    amounts of plasma FFA   that would otherwise   be cytotoxic. VLDL  is assembled in hepatocytes   in a two step   process that involves   the partial lipidation of a newly synthesized apoB- 100 , which   is an essential  structural component and does not participate in the subsequent   intravascular  remodeling  of the lipoprotein  particle whereas the  availability of  core  triglyceride   varies   considerably and determines the size and  possibly also the metabolic fate of VLDL  . Fatty acids used  for hepatic triglyceride  synthesis   originate  primarily from th systemic   plasma FFA pool as well as from   several   other   non systemic  fatty   acid sources such as hepatic   de novo lipgenesis  , and lipolysis of  intrahepatic     and   visceral    at triglyceride. Dysregulation of VLDL   metabolism   can lead  to increased   plasma  VLDL  triglyceride   concentration  greater number of circulating  VLDL  particles    and large triglyceride rich VLDL   all of which  are associated with increased  risk for   cardiovascular disease.

I am ignorant about female psychology, love and their affinity, dependency, more bondage & affection to HPO axis !!!! Effects of female obesity on the endocrinology and function of the hypothalamic pituitary   ovarian axis. Please don’t ask me how & why F gonad and different systems are much governed by HP axis. I am governed by good foods only!!!! 

 The association    between  obesity    and infertility  is partially  related   to oligo   ovulation or anovulation   PCOS   is commonly associated  with ovulatory    dysfunction hyperandrogenemia and PCOS   appearing ovaries   on ultrasound    and frequently is associated   with BMI   values greater   than 25   kg/ m . In addition   obese   PCOS   women have   higher rates   of anovulation    than leaner  patients who have the same   diagnosis   and the response   and doses   used for   induction  of ovulation   also are higher with suboptimal   ovulatory responses. An additional    barrier   to adequate   response   to  ovulation   induction  medications  is the hyperinsulinemia    and insulin  resistance   associated  with   the increase   in fat   in particular    the abdominal   phenotype    of obesity which defines   it as a condition  of relative  functional  hyperandrogenism  . Adipose   tissue  also is able   to store lipid soluble steroids including androgens   which seem   preferentially concentrated within  the adipose  tissue rather   than in the blood. Therefore  because  there is  more   abundant fat tissue   rather than   blood  in obese patients steroid   concentrations are greater  than in normal weight   individuals. Furthermore  fat represents  a site of intense  sex hormone   metabolism   resulting   from  steroidogenic    enzymes  such as   3B   dehydrogenase 17 B  hydroxydehydrogenase and    aromatase. Estradiol levels   from   increased   peripheral   aromatization   of androgens   also have a direct negative effect on the  hypothalamus  modifying  GnRH   pulsatility and reducing gonadotropins  at the pituitary  . The subsequent  relative   hypogonadotropic   environment   result in   anovulation .

  Insulin has  a negative   effect on the synthesis of  SHBG   by the liver   truncal obesity is associated   with insulin resistance    and increases in free  testosterone and  dihydrotestosterone. Levels    of SHBG  air regulated  by other   complex   factors including estrogens iodo thyronines   and growth hormone as stimulating   agents   and androgens and  insulin as inhibiting  factors. Insulin binds    with low   affinity to the LH   receptor  in the  theca cell and hyperinsulinemia   may stimulate  compensatory ovarian theca   cell   steroidogenesis and androgen production via   the saturation of the receptor which    may inhibit   normal ovulation via premature follicular atresia and premature  luteinization . Part  of the new Rotterdam criteria   for the diagnosis  of PCOS    includes the ultrasound appearance   of PCOS  appearing   ovaries where abundant follicles  at the antral  stage  in the ovarian a cortex are responsible  for this endocrine milieu. Follicular    development may  be affected by increased reactive   oxygen   species. In addition   leptin a surrogate marker   for fat mass  can directly modulate   granulosa   theca  and interstitial    cells with    inhibition  jof steroidogenesis  and  oocyte   maturation   thereby   providing  an additional  potential  mechanism   for anovulation .

What is The endocannaboid system???? The endocannaboid system also plays  a pivotal role in the anovulation    of obesity  . Its  primary negative   effect is in the hypothalamus although some down regulating influences may be  mediated directly at the      level of the pituitary and  ovary . By   suppressing   the secretory    pulsatility of  LH  endocannabinoids   can down regulate     serum LH   levels but   administration   of gonadotropins  of pulsatile GnRH    can restore ovulation    and LH  release. These effects   are  mediated by neurotransmitters known   to facilitate GnRH   secretion such as   norepinephrine   and glutamate   and by stimulating those modulators   known to down  regulate   GnRH   secretion   such as dopamine   Y  aminobutyric acid opioids   and corticotrophin releasing  hormone.  

                                                                           

All right .You are like me. Sleep up to 09 00 hrs. !! That’s fine. U are also like me  weighing 130 kg only!!! No problem. Mai hu na!!!  What are then the most commonly used  Anti  Obesity Drug ??

Orlistat is the drug I am ingesting from the age of six months!!! .Because  it acts as Lipase  inhibitor   by which it exerts anti  obesity Action : The Indications & Doses :  Obesity  : orally :for  adults like me  120 mg TID   with each main meal containing  fat  and it includes for weight   loss & management    when used in conjunction  with   a reduced  calorie  & low fat   diet.

Drug   safety : Hypersensitivity    chronic malabsorption  syndrome / cholestasis [ S/p : history   of hyperoxaluria  /Ca   oxalate    nephrolithiasis type ll DM] ADR: Serious : HTN   others : GI disturbances  fecal   urgency &   incontinence  , flatulence , fatty   stools / discharge , anxiety  fatigue menstrual  irregularities , increased risk  of breast cancer,   headache [ DDl ;Vit E/ Amiodarone absorption   reduced : Coumarins absorption reduced   that leads to  increase in INR , ACEls  increase  in BP . Hormonal  contraceptives risk of   contraceptive   failure   is increased  [  Monitor  BMI , diet   (calorie   & fat  intake )  serum glucose  , TFT , LFTs.