Barocrinology: The Endocrinology of Obesity from Bench to Bedside
Round 1
Reviewer 1 Report
I read with interest the manuscript of Kalra et al. regarding the main endocrine and metabolic elements of weight physiology and pathology.
The manuscript is interesting and a very comprehensive narrative review. I have only some minor points:
- in table 3, the use of “Syndromic obesity” in the "gland" cell is not appropriate and it should be replaced with another term
- in table 6, why didn't the authors also include liraglutide 3 mg?
- in table 7, I am not sure that metformin can effectively provide weight loss, usually it is neutral on weight
Author Response
Reviewer 1:
- I read with interest the manuscript of Kalra et al. regarding the main endocrine and metabolic elements of weight physiology and pathology.
The manuscript is interesting and a very comprehensive narrative review. I have only some minor points:
We thank the reviewer for the positive comments.
- - in table 3, the use of “Syndromic obesity” in the "gland" cell is not appropriate and it should be replaced with another term
We thank the reviewer for pointing this error. We have now replaced the term “Syndromic obesity” to “Hypothalamus” in Table 3.
- - in table 6, why didn't the authors also include liraglutide 3 mg?
We agree with this point and have now included the same as below
|
Drug |
Mechanism of action |
Common adverse effects |
Warnings |
Contraindications |
|
Liraglutide (3 mg) |
GLP-I Analogue |
Hypoglycemia, nausea, diarrhea, vomiting, constipation, dyspepsia, decreased appetite, headache, fatigue, dizziness, abdominal pain, and |
Serious hypoglycemia, thyroid C-cell tumors, acute gallbladder disease, acute pancreatitis, hypersensitivity reactions. |
Personal or family history of MTC or MEN syndrome type 2, hypersensitivity to liraglutide, Pregnancy y |
|
Added to abbreviations: MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; |
||||
- - in table 7, I am not sure that metformin can effectively provide weight loss, usually it is neutral on weight
We agree and thank the reviewer for this comment.
We have removed this from the table.
|
Medications |
Weight profile |
|
Antidiabetes |
Metformin, GLP-1 analogs (eg, exenatide, albiglutide, dulaglutide, semaglutide and liraglutide) or SGLT-2 inhibitors (dapagliflozin, empagliflozin and canagliflozin) promote weight loss Basal insulin causes less weight gain than other insulin types |
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The review presented by Sanjay Kalra, et al. entitled: “Barocrinology: The Endocrinology of Obesity from Bench to Bedside” and submitted to revision, tackles very interesting aspects related to obesity bariatric and pharmacological management and the endocrinology. I think this article should be accepted for publication with minimal changes since it summarizes and contributes significantly to overall knowledge in this disease. The paper is well-written although, changes minimal must be included to sustain the quality of the manuscript.
Table 2: check the table, there is a mistake
Line 87: check the paragraph.
Table 3: it is based on an only reference and should be presented a little more clearly because it leads to error
Line 194: Say it is MNT
Line 252 and 253: I think is better to say antidiabetics and antihistaminics
Author Response
Reviewer 2:
- The review presented by Sanjay Kalra, et al. entitled: “Barocrinology: The Endocrinology of Obesity from Bench to Bedside” and submitted to revision, tackles very interesting aspects related to obesity bariatric and pharmacological management and the endocrinology. I think this article should be accepted for publication with minimal changes since it summarizes and contributes significantly to overall knowledge in this disease. The paper is well-written although, changes minimal must be included to sustain the quality of the manuscript.
We thank the reviewer for the positive comments.
- Table 2: check the table, there is a mistake
We have modified the errors in the table as below:
Table 2. Hormonal changes in obesity and after weight-loss9,10,113.
|
Hormone |
Obesity |
Proposed pathophysiology in obesity |
Weight-loss /Fasting |
|
Pituitary |
|
||
|
Prolactin |
|
|
|
|
Basal prolactin |
N |
|
N |
|
Prolactin response to hypoglycemia |
N/↓ |
|
N/↓ |
|
Prolactin response to TRH |
N/↓ |
|
N |
|
GH/IGF-I |
|
||
|
GH |
N/↓ |
↓↑GHRH, ↑GH-BP, ↑insulin, ↓ghrelin, ↑somatostatin
|
↑ |
|
GH production rate |
↓ |
|
↑ |
|
GH metabolic rate |
↑ |
|
|
|
GH response to GHRH |
↓ |
|
N/↓ |
|
GH response to hypoglycemia |
↓ |
|
N/↓ |
|
IGF-I |
N/↓ |
I↑GH sensitivity t↑intrahepatic triglyceride content |
|
|
Free IGF-I |
↑ |
|
|
|
IGFBP-3 |
N/↑ |
|
|
|
HPA axis in obesity |
|
||
|
Basal cortisol (blood and salivary)
|
N |
↑↑CRH, ↑ adipose 11-HSD, ↓ CBG Altered suppression tests due to hyperactivity of the HPA axis
|
|
|
Urinary free cortisol |
N/↑ |
|
|
|
Basal ACTH |
N/↑ |
↑CRH |
|
|
Cortisol production rate |
↑ |
|
|
|
Cortisol metabolic rate |
↑ |
|
|
|
17-OH-corticosteroids |
↑ |
|
|
|
HPA axis response to stimulatory tests in central obesity |
|
||
|
Cortisol after CRH |
↑ |
|
N |
|
ACTH after CRH |
↑ |
|
↑ |
|
Cortisol after tetracosactide |
↑ |
|
|
|
Cortisol after hypoglycemia |
↑ |
|
|
|
Thyroid |
|
||
|
FT4 |
N/slight ↓ |
↑↑disposal
|
N |
|
T3 |
↑ |
Probably related to the amount of food intake and not to obesity itself. (kkoris ref nos 8-12) |
↓ |
|
rT3 |
↓ |
↑ |
|
|
TSH |
N/↑ |
↑↑leptin and insulin ↑ peripheral T4 disposal |
N |
|
TSH after TRH |
N/↑/↓ |
|
TRH dose decreases |
|
Parathyroid |
|
||
|
PTH |
N/↑ |
Secondary due to vitamin D deficiency
|
|
|
|
PTH ↑ calcium ↓ phosphate ↑ |
Pseudohypoparathyroidism Type 1a (Albright hereditary osteodystrophy) |
|
|
Pancreas/Gut |
|
||
|
Insulin |
↑ |
IInsulin resistance Insulinoma nsulinomae istanc
|
↓ with decreased insulin resistance |
|
Ghrelin
|
↓ |
Lack of ghrelin decrease after meals
|
↑ |
|
GLP-1
|
↓ |
↑ FFA, microbiota
|
↑ |
|
Gonads |
|
||
|
Testosterone (male)
|
↓ |
↓SHBG, ↑ aromatase, ↓GnRH
|
↑ testosterone and gonadotrophins, ↓ estradiol |
|
Testosterone (female)
|
↑ |
Insulin resistance (PCOS) ↓ SHBG
|
↓ serum total testosterone, androsterone and sulfate dehydroepiandrosterone (DHEA) |
|
LH/FSH(male) |
↓ |
↑oestrogens/androgens
|
↑ SHBG, LH, and FSH |
|
LH/FSH(female) |
↑ LH |
Insulin resistance
|
↑ Serum estradiol, FSH and SHBG |
|
Adrenal |
|
||
|
Renin |
↑ |
↑ Sympathetic tone
|
|
|
Aldosterone |
↑ |
↑ Adipokines, renin- angiotensin, leptin
|
|
|
Adipocyte |
|
||
|
Leptin |
↑ |
↑ adipose mass, Leptin resistance
|
↓ |
|
Abbreviations: 11-HSD, 11β-hydroxysteroid dehydrogenase; ACTH, adrenocorticotropic hormone; CBG, corticosteroid-binding globulin; CRH, corticotropin-releasing hormone; FFA, free fatty acids; FSH, follicle-stimulating hormone; FT4, free thyroxine; GH-BP, growth hormone-binding protein; GHRH, growth hormone-releasing hormone; GLP, glucagon-like peptide; GnRH, gonadotropin-releasing hormone; HPA, hypothalamic–pituitary–adrenal axis; IGF, insulin-like growth factor; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; PTH, parathyroid hormone; SHBG, sex hormone-binding globulin; TSH, thyroid-stimulating hormone |
|||
- Line 87: check the paragraph.
We have now corrected the same.
3.1. Endocrine condition: laboratory evaluation: dos and don’ts
Laboratory evaluation for endocrinopathies in a patient with obesity
4. Table 3: it is based on an only reference and should be presented a little more clearly because it leads to error
Thanks for the feedback. All the references used in the table have been mentioned in the table header
Table 3. Endocrine evaluation in obesity10,12–14.
|
Gland |
Prevalence in obesity |
When to assess |
First diagnostic procedure |
Other possible work up in obesity |
Not recommended in obesity |
||
|
Thyroid (Same TSH and thyroid hormone values should be used in patients with obesity as are used in normal population without obesity) |
Severe hypothyroidism is rare but subclinical hypothyroidism is common. It is important to render the patient Euthyroid prior to embarking on weight loss therapy to enhance maximum effect of treatment |
Thyroid function should be tested for all patients with obesity
|
TSH |
free T4 and antibodies (anti-TPO) should be measured only if TSH is elevated |
Routine FT3 in patients with elevated TSH
Routine ultrasound of the thyroid gland (irrespective of thyroid function) |
||
|
Adrenal (same normal values should be applied patients with obesity as are used in normal population without obesity) |
Cushing’s disease or Cushing’s syndrome is rare But exogenous cushings syndrome is common. |
Central obesity Hypertension Type 2 diabetes Purplish striae Facial plethora Easy bruisability Testing for hypercortisolism should be considered in patients going for bariatric surgery |
8 am cortisol (to rule out exogenous steroid intake) 1 mg ODST |
24-h urine cortisol or late-night salivary cortisol in patients with positive 1 mg overnight dexamethasone suppression test
Imaging (find the cause/source) and ACTH in patients with confirmed hypercortisolism |
Routine testing for hypercortisolism |
||
|
Drug-induced adrenal dysfunction (e.g. anti-depressants, antipsychotics, glucocorticoids, etc) is common |
Biochemical testing should be performed in patients with clinical suspicion of hypercortisolism; those undergoing bariatric surgery, or having psychiatric disorders
|
8 am cortisol |
|
Testing for exogenous hypercortisolism in patients using corticosteroids |
|||
|
Male Gonad (Use age-specific reference ranges for testosterone |
Androgen deficiency is common |
In elderly male with impaired social and mental health, less energy |
|
Total and free testosterone (or calculated), SHBG in patients with clinical features of hypogonadism |
Routine biochemical testing for hypogonadism unless key clinical symptoms/signs of hypogonadism and in elderly with impaired social/mental health, less energy |
||
|
Female Gonad |
Androgen excess is common |
Central obesity Irregular menses Hirsutism Acanthosis nigricans chronic anovulation/infertility |
LH, FSH, estradiol, testosterone |
Total testosterone, SHBG, Δ 4androstenedione, 17-hydroxyprogesterone and prolactin in patients with menstrual irregularities (assess in early follicular phase if menstrual cycle is predictable) |
Routine testing for gonadal dysfunction |
||
|
|
Clinical features of PCOS |
Total testosterone, free T, Δ 4androstenedion, SHBG and blood glucose |
Ovarian morphology |
||||
|
Premature ovarian failure is uncommon |
Secondary amenorrhea Vasomotor symptoms |
LH, FSH, estradiol |
Progesterone and prolactin in patients with anovulation |
||||
|
Physiological ovarian failure in menopause is common |
Vaginal mucosal atrophy |
LH, FSH, estradiol |
|||||
|
Pituitary |
GH deficiency is rare |
Hypothalamic or pituitary disease, pituitary or hypothalamic surgery or radiation therapy |
|
IGF1/GH using a dynamic test only in patients with suspected hypopituitarism |
Routine testing for IGF1/GH |
||
|
|
Hypopituitarism is rare |
Suspicion of hypothalamic obesity Surgery or radiotherapy in pituitary region |
FT4 TSH LH FSH (testosterone or estradiol) GH IGF-1 PRL ACTH stimulation test GH stimulation test |
|
|
||
|
|
Acquired hypothalamic obesity (hypothalamic lesions or, tumors) is rare |
Severe hyperphagia Possible multiple endocrine abnormalities |
Brain CT/MRI |
|
|
||
|
Parathyroid |
Pseudohypoparathyroidism Type 1a (Albright hereditary osteodystrophy) is rare |
Short stature, short fourth metacarpal bones, obesity, sc calcifications, developmental delay |
PTH ↑ calcium ↓ phosphate ↑ |
|
Routine testing for hyperparathyroidism or Vitamin D deficiency |
||
|
Hypothalamus |
Hypothalamic obesity associated with Genetic Syndromes is very rare |
Hypogonadism (hypogonadism or hypergonadotropic) or variable gonadal function. dysmorphic syndrome, mental and grow retardation |
Leptin (leptin resistance);genetic testing |
Routine testing of hormones such as leptin and ghrelin in patients with suspicion of syndromic obesity |
|
||
|
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; FT4, free thyroxine; GH, growth hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; MC4R, melanocortin receptor 4; ODST, overnight dexamethasone suppression test; PCSK, proprotein convertase subtilisin/kexin; PTH, parathyroid hormone; sc, subcutaneous; TSH, thyroid-stimulating hormone |
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5.Line 194: Say it is MNT
We have modified this line as suggested
5.1. Potential endocrine/metabolic impact of formula MNT
5.1 Medical Nutrition Therapy (MNT)
- Line 252 and 253: I think is better to say antidiabetics and antihistaminics
We have modified the same
Common medications likely to cause weight gain include antipsychotics, antidiabetics, antihypertensives, antidepressants, antihistaminics etc. Medications, that are either weight neutral or have weight loss as a side effect, should be preferred over medications that have weight gain as a side effect
These have been added. Dr Punit-these are not to be included in the journal comment reply
In addition if could please do two small changes –
Replace reference 19 with this - Kapoor N, Jiwanmall SA, Nandyal MB, Kattula D, Paravathareddy S, Paul TV, Furler J, Oldenburg B, Thomas N. Metabolic Score for Visceral Fat (METS-VF) Estimation - A Novel Cost-Effective Obesity Indicator for Visceral Adipose Tissue Estimation. Diabetes Metab Syndr Obes. 2020 Sep 16;13:3261-3267. doi: 10.2147/DMSO.S266277. PMID: 32982356; PMCID: PMC7507406.
For line 101-103, if could add the following two references –
Atri A, Jiwanmall SA, Nandyal MB, Kattula D, Paravathareddy S, Paul TV, Thomas N, Kapoor N. The Prevalence and Predictors of Non-alcoholic Fatty Liver Disease in Morbidly Obese Women - A Cross-sectional Study from Southern India. Eur Endocrinol. 2020 Oct;16(2):152-155. doi: 10.17925/EE.2020.16.2.152. Epub 2020 Oct 6. PMID: 33117448; PMCID: PMC7572172.
Ramasamy S, Joseph M, Jiwanmall SA, Kattula D, Nandyal MB, Abraham V, Samarasam I, Paravathareddy S, Paul TV, Rajaratnam S, Thomas N, Kapoor N. Obesity Indicators and Health-related Quality of Life - Insights from a Cohort of Morbidly Obese, Middle-aged South Indian Women. Eur Endocrinol. 2020 Oct;16(2):148-151. doi: 10.17925/EE.2020.16.2.148. Epub 2020 Oct 6. PMID: 33117447; PMCID: PMC7572161.
Author Response File: Author Response.pdf
