What Happens When a Person Loses Fat TISSUE (not just fat) Completely

choi

Gina Kolata, Invisibly Obese. New York Times, July 26, 2016.
www.nytimes.com/2016/07/26/health/skinny-fat.html

two consecutive paragraphs:

"Leptin is released by fat cells and travels through the blood to the brain. The more fat on a person's body, the more leptin is released. When fat levels are low, leptin levels in the brain are low, and the brain responds by increasing the person's appetite, prompting the person to eat and gain weight. For someone like Ms [Claire] Johnson[-Walker], who has almost no fat cells to signal the brain, the brain gets almost no leptin. To the brain, it seems as if she is starving. As a result, she receives continuous signals to eat.

"With leptin treatment, Ms Johnson's brain was tricked into responding as though she had abundant fat. Her insatiable hunger vanished. Fat disappeared from her liver, her blood glucose became normal, and so did her cholesterol and triglyceride levels.


Note:
(a) The thin but ravenous Claire Walker Johnson, 55, of Queens was born in Jamaica. "After coming to the United States as a college student, she saw a doctor for some bumps on her arms and was stunned to learn that they were cholesterol crystallizing from her blood. Her cholesterol level was sky high. * * * [measurement of] Ms Johnson: 5 feet 7 inches. She weighed her: 119 pounds."

Xanthelasma
https://en.wikipedia.org/wiki/Xanthelasma
(a kind of xanthoma; section 2 Name)

choi

(b) "Simeon Taylor, who was the chief of the diabetes branch at the National Institute of Diabetes and Digestive and Kidney Diseases, popped up from his chair. He had seen several patients like Ms Johnson. They have lipodystrophy, he said, a rare genetic disorder that is characterized by an abnormal lack of fatty tissue."
(i) Leptin as a Treatment for Generalized Lipodystrophy: a Translational Success Story. National Institute of Diabetes and Digestive and Kidney Diseases, Apr 6, 2016
https://www.niddk.nih.gov/news/r ... -lipodystrophy.aspx
(a clinical study to treat congenital lipodystrophy with leptin, which appears successful)

Quote: "Lipodystrophy is actually a group of disorders with disparate origins but with a common set of metabolic consequences. Lipodystrophy can either be genetic or acquired, and can be generalized (near total lack of fat) or partial (fat loss in certain parts of the body). While lipodystrophy is characterized by the loss of fatty tissue in certain areas of the body, tissues such as liver and muscle exhibit significant abnormal accumulation of fat, which impairs metabolic activity. People with the disorder also exhibit resistance to the effects of insulin and are thus at high risk of developing diabetes. They may also have a range of lipid abnormalities [for example: high lipid in blood].
(ii)
(A) lipo- (prefix; from Ancient Greek lípos animal fat)
https://en.wiktionary.org/wiki/lipo-
(B) dystrophy
https://en.wikipedia.org/wiki/Dystrophy
(is the degeneration of tissue)

A phenomenon known to most is a muscle undergoes dystrophy when it loses innervation (connection to a nerve). Examples are:
stroke and spinal cord injury (which eliminates the nerve cells which is a step higher than the nerve cell -- called motor neurons which are found in spinal cord -- actually innervates the muscle);
as well as poliomyelitis (caused by poliovirus) that kills motor neurons.

Malnutrition also brings about dystrophy of all organs.
(iii) Wait to read (c) about leptin.
(iv) The (b) says Claire Walker Johnson suffers from lipodystrophy. What form of lipodystrophy? Congenital or acquired? How?
(A) I google her name and find this NYT report only.
(B) It turns out that she is not really called Claire Walker Johnson. Da-da (here is the introduction).

Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Meeting. Center for Drug Evaluation and Research, Dec 1, 2013.
www.fda.gov/downloads/AdvisoryCo ... ittee/UCM388935.pdf

Quote:

* purpose of the meeting:

"Today's agenda involves discussion of biological license application 125390 for metreleptin injection, sponsored by Amylin Pharmaceuticals, a wholly-owned subsidiary of Bristol-Myers Squibb." page 19

"The sponsor is seeking approval of metreleptin for the treatment of pediatric and adult patients with generalized lipodystrophy or a metabolic disorder associated with partial lipodystrophy, including  hypertriglyceridemia and/or diabetes mellitus inadequately controlled, on a current therapy, and/or evidence of hepatic steatosis." page 21

* "MS JOHNSON-WALKER: My name is Claire Burke, otherwise known as Claire Johnson-Walker. I have no financial interests. I am one of the patients in the leptin trial at NIH." page 281

"As I tell you, my name is Claire Burke. I was born in Jamaica with skin disease, but I live in New York for more than 20 years. I am a radiologic technologist by profession. Both parents are carriers of the AGP2 [sic] mutation and they [each] passed the mutation on to me [an AGPAT 2 mutation is autosomal recessive]. I have the congenital generalized form of lipodystrophy. I am one of the patients in the trial, as I told you, from September 4th of 2001. Leptin is the only drug of choice to treat my metabolic disorder, as all the other drugs failed to do so." page 282

choi

(c) Cortés VA and Fernández-Galilea M, Lipodystrophies: Adipose Tissue Disorders with Severe Metabolic Implications. Journal of Physiology and Biochemistry, 71: 471–478 (2015)
http://link.springer.com/article/10.1007%2Fs13105-015-0404-1

Quote:

"Lipodystrophy encompass a group of heterogeneous disorders consisting in marked reduction, absence, and/or the redistribution of adipose tissue. * * * Etiologically, they can be congenital or acquired. * * * Lipodystrophic patients have severe reduction of white adipose tissue (WAT) mass

"The pathophysiological basis of these metabolic complications remains unclear; however, the absence or dysfunction of white adipocytes in these subjects determines accumulation of lipids in non-adipose cells [such as liver]. This ectopic lipid depot results in lipotoxicity, a proposed mechanism for insulin resistance.

"Primary [ie, congenital] lipodystrophies are infrequent conditions. There are ~1000 patients reported with inherited forms of lipodystrophy and the combined overall prevalence of these diseases [congenital and acquired] is estimated to be 1 in 1,000,000 subjects.

"Inherited lipodystrophies can be generalized or partial (Table 1). * * * There are four congenital generalized lipodystrophy (CGL) syndromes described, all of them with an autosomal recessive pattern of transmission. [In Table 1 is Berardinelli-Seip syndrome, with four types -- each with its own mutation; type 1 has a mutation in AGPAT2]

(i) AGPAT 2
http://www.ncbi.nlm.nih.gov/gene/10555
(whose full name is "1-acylglycerol-3-phosphate O-acyltransferase 2")

"summary": The gene encoding a protein that "converts lysophosphatidic acid to phosphatidic acid, the second step in de novo phospholipid biosynthesis. Mutations in this gene have been associated with congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, a disease characterized by a near absence of adipose tissue and severe insulin resistance.

(ii) phosphatidic acid
https://en.wikipedia.org/wiki/Phosphatidic_acid
(section 2 Formation and degradation: The "acyl transferase II" in the graphic is the enzyme AGPAT2, described immediately above)
(iii) "The mechanisms underlying the loss of adipose tissue in Agpat2−/− mice remain unknown."
Cautivo KN et al, AGPAT2 Is Essential for Postnatal Development and Maintenance of White and Brown Adipose Tissue. Molecular Metabolism, 5: 491–505 (July 2016)
www.ncbi.nlm.nih.gov/pmc/articles/PMC4921804/

choi

(d) The leptin and its receptor, which is conceptually similar to key and lock, respectively.
(i) leptin
https://en.wikipedia.org/wiki/Leptin
(A) How the mutation (ob, the first two letters of the adjective obese) was identified: "In 1949, a non-obese mouse colony being studied at the Jackson Laboratory [in Maine] produced a strain of obese offspring"
(B) Fast forward: The gene responsible for mutation was cloned, which was named leptin: "from the Greek lepto meaning thin"  (both quoting the Wiki page)
(C) Fundamentally, adipose tissue (the biological term for "fat" as a noun) secrets leptin to tell brain (specifically hypothalamus 下視丘) that "we adipose tissue has enough fat in storage. So please stop eating."  (Thus leptin is by definition a hormone.)
(ii) three-dimentional structures:

Mancour LV et al, Ligand-Induced Architecture of the Leptin Receptor Signaling Complex. Molecular Cell, 48: 655–661 (2012)
www.cell.com/molecular-cell/abstract/S1097-2765(12)00779-4
(Here, we applied single-particle electron microscopy (EM) to characterize the architecture of the extracellular region of LEP-R alone and in complex with leptin; "Geographic Abstract")

You will not comprehend the following unless you are a PhD in biology: Structurally (3-D), "leptin is classified as a member of the long-chain cytokine family * * * the LR can be classified as a class I cytokine receptor."  
Peelman T et al, 20 Years of Leptin; Insights into signaling assemblies of the leptin receptor. Journal of Endocrinology (JOE), 223: T9-T23 (2014).
joe.endocrinology-journals.org/content/223/1/T9.full
(iii) Coppari R and Bjørbæk C, Leptin Revisited: Its Mechanism of Action and Potential for Treating Diabetes. Nature Reviews Drug Discovery, 11: 692-708 (2012)
http://www.nature.com/nrd/journal/v11/n9/execsumm/nrd3757.html
(executive summary)

Quote: "we first discuss data from leptin-based clinical trials [on humans]. The results from these trials indicate that leptin therapy fails to improve metabolic defects in people who have elevated levels of circulating leptin [ie, those who are obese without an obvious genetic mutation because he eats too much] and hence are leptin-resistant. Conversely, regardless of the disease context, leptin therapy is very effective in improving metabolic imbalances in individuals who have severe hypoleptinaemia [meaning lower leptin level than normal persons; eg in CGL patients, lacking fat, produces not leptin].

* To view full text (for free; but you need not to read it), in the top horizontal bar, click "Full text" to the left og "At a glance."

(e) "Dr Marc Reitman * * * and * * * Dr Charles Vinson * * * genetically engineered mice to have lipodystrophy. The mice, like Ms Johnson, had almost no fat tissue. And like her, they developed all of the conditions associated with obesity."
(i) They produced two kinds of mice as animal model of lipodystrophy, each involving a gene that is not the mouse equivalent of human AGPAT2.
(ii) There is no need to read the NYT report further, full of unproven ideas.